Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([Si](C)(C)C)=[C:7]2[CH2:17][CH2:18][O:19][Si](C(C)(C)C)(C)C)([O-:3])=[O:2].C([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:17][CH2:18][OH:19])([O-:3])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)OCCc1c([Si](C)(C)C)[nH]c2ccc([N+](=O)[O-])cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc2[nH]cc(CCO)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
To a solution of 5-nitro-2-trimethylsilyl-3-(2-t-butyldimethylsiloxyethyl)indole (7.30 g, 0.019 mol) in 125 mL of acetonitrile was added 48% HF (3.0 mL, 0.084 mol) and the mixture was stirred at room temperature for 1 h. Another 2.5 mL (0.07 mol) of 48% HF was added and stirring was continued for 18 h. The mixture was then cautiously basified with saturated aqueous Na2CO3 and extracted with ethyl acetate. The organic extract was washed (brine), dried (Na2SO4) and evaporated to give a gum. This material was triturated with ether and the supernatant was evaporated to give a gum. Chromatography (SiO2 /hexane-ethyl acetate, 1:1) of this gum gave the title compound (2.24 g, 57%) as a solid, mp 90° C.: IR (neat) 3380 (br), 1622, 1330 cm-1 ; 1H NMR (CDCl3, 200 MHz) δ8.60 (d, J=1.7 Hz, 1 H), 8.48 (br s, 1H), 8.12 (dd, J=9.0, 1.7 Hz, 1H), 7.40 (d, J=9.0 Hz, 1H), 3.96 (t, J=6.3 Hz, 2H), 3.07 (t, J=6.3 Hz, 2H), 1.56 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[N:14]=[CH:13][C:12]([CH:18]=C)=[CH:11][C:10]=3[C:9]2=[O:20])=[CH:5][CH:4]=1.C(Cl)Cl.C[OH:27]>>[OH:27][CH2:18][C:12]1[CH:13]=[N:14][C:15]2[CH2:16][CH2:17][N:8]([CH2:7][C:6]3[CH:21]=[CH:22][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:9](=[O:20])[C:10]=2[CH:11]=1
Reactant: C=Cc1cnc2c(c1)C(=O)N(Cc1ccc(OC)cc1)CC2
Reactant: CO
Solvent: ClCCl
Product: COc1ccc(CN2CCc3ncc(CO)cc3C2=O)cc1
Reaction time: 0.33 h

Procedure:
6-(4-Methoxybenzyl)-3-vinyl-7,8-dihydro-1,6-naphthyridin-5(6H)-one (800 mg, 4.23 mmol) was dissolved in 1:1 MeOH:DCM (50 mL) and cooled in a dry ice/acetone bath. A stream of O3 was bubbled through for 20 min. At this time LC-MS indicated complete consumption of starting material. Oxygen was passed through the solution for 20 min, and then NaBH4 (500 mg) was added to the solution and the cold bath removed. After 20 min, Rochelle's salt (20%, 5 mL) was added to the reaction mixture. The mixture was concentrated and re-suspended into EtOAc (50 mL) and dried over MgSO4. The filtrate was concentrated and used directly in the next step without further purification (800 mg, 98%). LC-MS (M+H) =299.1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([N:24]3[CH2:29][CH2:28][CH:27]([N:30]4[C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=5[CH2:33][O:32][C:31]4=[O:40])[CH2:26][CH2:25]3)=[O:23])=[C:17]([C:41]([F:44])([F:43])[F:42])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CCOC(C)=O>[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([N:24]3[CH2:25][CH2:26][CH:27]([N:30]4[C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=5[CH2:33][O:32][C:31]4=[O:40])[CH2:28][CH2:29]3)=[O:23])=[C:17]([C:41]([F:44])([F:42])[F:43])[CH:16]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CC(=O)N3CCC(N4C(=O)OCc5ccccc54)CC3)c(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(OC2CCNCC2)cc1C(F)(F)F)N1CCC(N2C(=O)OCc3ccccc32)CC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Into a stirred solution of 1-(1-(4-(1-tert-butyloxycarbonyl-4-piperidinyloxy)-2-(trifluoromethyl)phenylacetyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one (0.35 g, 0.51 mmol) from Step 7 above in EtOAc (25 mL) at 0° C. was bubbled HCl gas for 15 min. The resulting suspension was stirred at 0° C. for 45 min. Excess HCl was removed by bubbling argon though the mixture for 15 min. The solvent was removed under reduced pressure and the residue was dissolved in CH2Cl2. The solvent was evaporated under reduced pressure to give the hydrochloride salt of the title compound as an amorphous solid.
Reaction SMILES: [B:1]([OH:4])([OH:3])[OH:2].[Cl-].[K+].[OH-].[K+].[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([S:16]([NH:19][Cl:20])(=[O:18])=[O:17])=[CH:14][CH:15]=1.[CH3:21][N:22]([CH3:31])[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1.S(=O)(=O)(O)[OH:33].O[N:38]1[CH2:45][CH2:44][CH2:43][C@H:39]1[C:40]([OH:42])=[O:41]>O.COCCO.C(O)C>[B:1]([OH:4])([OH:3])[OH:2].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:19][Cl:20])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[CH3:21][N:22]([CH3:31])[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1.[NH:38]1[CH2:45][C@H:44]([OH:33])[CH2:43][C@H:39]1[C:40]([OH:42])=[O:41]
Reactant: O=C(O)[C@@H]1CCCN1O
Reactant: O=S(=O)(O)O
Agent: CN(C)c1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: OB(O)O
Solvent: COCCO
Solvent: O
Solvent: CCO
Product: O=C(O)[C@@H]1C[C@@H](O)CN1

Procedure:
A boric acid buffer was prepared by dissolving 6.18 g of boric acid and 22.5 g of KCl in distilled water, adjusting at pH 8.7 with potassium hydroxide and making the total volume 100 ml. A chloramine T solution was prepared by dissolving 1.41 g of chloramine T (NACALAITESQUE, Catalog No.080-05) in 25 ml of 2-methoxyethanol (NACALAITESQUE, Catalog No.153-10). A p-dimethylaminobenzaldehyde solution was prepared by dissolving 12 g of p-dimethylaminobenzaldehyde (NACALAITESQUE, Catalog No.128-16) in 20 ml of ethanol followed by adding a mixture of 2.74 ml of concentrated sulfuric acid and 20 ml of ethanol slowly to the solution with cooling on ice. A hydroxyproline conventional solution was prepared by dissolving 3 mg of hydroxy-L-proline (NACALAITESQUE, Catalog No.188-17) in 1 ml of distilled water (3 mg/ml).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]=[CH:7][NH:6][C:5]2=[O:13].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[N:8]=[CH:7][NH:6][C:5]2=[O:13]
Reactant: O=c1[nH]cnc2cc(F)c(F)cc12
Reactant: C1COCCN1
Product: O=c1[nH]cnc2cc(N3CCOCC3)c(F)cc12
Temperature: 80 °C
Reaction time: 16 h
Yield: 74.8 %

Procedure:
37.2 g (0.20 mol) of 6,7-difluoro-3H-quinazolin-4-one were suspended in 70 ml (0.80 mol) of morpholine and stirred at an internal temperature of 80° C. for 16 h. Conventional work-up gave 37.3 g (Y=74%) of 6-fluoro-7-morpholin-4-yl-3H-quinazolin-4-one.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2[O:11][C:10]([CH:12]=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[N+:16]([CH3:19])([O-:18])=[O:17].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2[O:11][C:10](/[CH:12]=[CH:19]/[N+:16]([O-:18])=[O:17])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(Cc2ccc(F)cc2)o1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(Cc2ccc(F)cc2)o1
Temperature: 100 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
A mixture of 5-(4-fluoro-benzyl)-furan-2-carbaldehyde (1 g, 4.89 mmol) described in Manufacturing Example 208-1-2, nitromethane (1.32 mL, 24.5 mmol), ammonium acetate (754 mg, 9.78 mmol), and acetic acid (10 mL) was stirred for 3 hours at 100° C. This mixture was cooled to room temperature and partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (1.21 g). The title compound was used in the following reaction without any further purification.
Reaction SMILES: [C:1]1(C=CC(O)=CC=1)O.[O-2].[Ca+2].CC1C=C(O)C=CC=1O.CC1C(C)=C(C=CC=1O)O.[CH3:30][C:31]1[C:32]([OH:40])=[C:33]([CH3:39])[C:34]([CH3:38])=[C:35]([CH:37]=1)[OH:36]>CO>[CH3:30][C:31]1[C:32]([OH:40])=[C:33]([CH3:39])[C:34]([CH3:38])=[C:35]([OH:36])[C:37]=1[CH3:1]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: Oc1ccc(O)cc1
Agent: Cc1c(O)ccc(O)c1C
Agent: Cc1cc(O)ccc1O
Agent: [Ca+2]
Solvent: CO
Product: Cc1c(C)c(O)c(C)c(C)c1O
Temperature: 25 °C
Reaction time: 0.13 h

Procedure:
Into an autoclave (inner volume: 4.5 ml, made of SUS 316, without manometer) were charged 0.016 g of hydroquinone, 1.355 g of methanol and 2.5 mg of calcium oxide (manufactured by Wako Pure Chemical Ind., Ltd.). The reaction was started by elevating the temperature up to425° C. with sand bath. After 8 minutes, the autoclave was quickly cooled and the reaction solution was taken out from the autoclave when the temperature was cooled back to the room temperature. The measurement according to the process described above revealed that the conversion of hydroquinone was 87% by mole, the selectivity of monomethylhydroquinone was 30% by mole, the selectivity of dimethylhydroquinone was 42% by mole and the selectivity of trimethylhydroquinone was 18% by mole. As byproducts, tetramethylhydroquinone was produced with a selectivity of 3% by mole.
Reaction SMILES: [C:1]([NH:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([C@@H:19]3[O:23][C@H:22](/[CH:24]=[CH:25]/[P:26](=[O:33])([O:30]CC)[O:27]CC)[C@@H:21]([OH:34])[C@H:20]3[OH:35])[N:17]=[CH:18][C:11]=12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[Si](I)(C)(C)C>CC#N>[C:1]([NH:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([C@@H:19]3[O:23][C@H:22](/[CH:24]=[CH:25]/[P:26](=[O:27])([OH:30])[OH:33])[C@@H:21]([OH:34])[C@H:20]3[OH:35])[N:17]=[CH:18][C:11]=12)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=O)(/C=C/[C@H]1O[C@@H](n2ncc3c(NC(=O)c4ccccc4)ncnc32)[C@H](O)[C@@H]1O)OCC
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: O=C(Nc1ncnc2c1cnn2[C@@H]1O[C@H](/C=C/P(=O)(O)O)[C@@H](O)[C@H]1O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.8 %

Procedure:
Compound 25.1 (62.2 mg, 0.124 mmol) in CH3CN (1.25 mL, 0.1 M) was treated with 2,6-lutidine (215 μL, 1.85 mmol) and TMSI (176 μL, 1.24 mmol). The mixture was stirred at room temperature for 1 h and the solvent was removed in vacuo. The residue was treated with concentrated NH4OH (2 mL) and the solvent was removed in vacuo (×3). The residue was treated with 1% AcOH (2 mL) and treated to reverse phase HPLC to afford compound 25.2 (19.3 mg, 35% yield) as a white solid: MS (ESI) m/z 448 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:15][C:14]3[CH:16]=[C:17]([Cl:30])[C:18]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)(=[O:22])=[O:21])=[CH:19][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])C.C1COCC1.O[Li].O>O>[Cl:30][C:17]1[C:18]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:19][C:13]2[N:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]3)[NH:15][C:14]=2[CH:16]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(S(=O)(=O)c4ccc(Cl)cc4)c(Cl)cc3[nH]2)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnn(-c2nc3cc(S(=O)(=O)c4ccc(Cl)cc4)c(Cl)cc3[nH]2)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 95.8 %

Procedure:
To a mixture of 1-[6-chloro-5-(4-chloro-benzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (1.92 g, 4.13 mmol), THF (16 mL), and water (5 mL) was added LiOH.H2O (0.693 g, 16.5 mmol). The mixture was stirred for 18 h at 23° C. The solvent was evaporated, water (10 mL) was added and the mixture acidified with 1M HCl. The resulting precipitate was filtered and dried to yield the titled compound (1.73 g, 94%). MS (ESI/CI): mass calcd. for C17H10Cl2N4O4S, 436.0; m/z found, 437.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 8.89 (s, 1H), 8.40 (s, 1H), 8.25 (s, 1H), 7.93-7.90 (m, 2H), 7.69-7.66 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:22])=[CH:4][C:5]([F:21])=[C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])[CH:7]=1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28](Cl)=[O:29]>N1C=CC=CC=1>[Cl:22][C:3]1[C:2]([NH:1][C:28](=[O:29])[C:24]2[S:23][CH:27]=[CH:26][CH:25]=2)=[CH:7][C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[C:5]([F:21])[CH:4]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N)c(Cl)cc2F)c1=O
Reactant: O=C(Cl)c1cccs1
Solvent: c1ccncc1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(NC(=O)c3cccs3)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
In 5 ml of pyridine was dissolved 0.34 g of 3-(5-amino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, and 0.17 g of 2-thiophencarbonyl chloride was added thereto at 5° C. or lower. Thereafter, the temperature was increased to room temperature and the reaction was continued overnight. Then, pyridine was removed by distillation and the residue was dissolved in ethyl acetate. The solution was washed successively with water, diluted hydrochloric acid and a saturated saline solution, and dried over anhydrous sodium sulfate followed by removing ethyl acetate by distillation to obtain a crude product. This was washed with diisopropyl ether to obtain 0.30 g of the desired compound as white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:16][CH2:15][N:14](C(OCC)=O)[CH2:13][CH2:12]3)[C:6]=2[CH:22]=1.[OH-].[Na+]>Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[C:6]=2[CH:22]=1
Reactant: CCOC(=O)N1CCC(n2c(=O)[nH]c3ccc(Cl)cc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c2ccc(Cl)cc2n1C1CCNCC1
Temperature: 0 °C
Yield: 76.2 %

Procedure:
D7 (12.0 g, 37 mmol) was suspended in a 2.5 M aqueous solution of sodium hydroxide (150 mL). The suspension was refluxed for 15 hours and then allowed to cool. The solution was acidified with 6 M HCl (˜70 mL) until no more effervescence was observed (˜pH 2) and then the pH was carefully adjusted to pH 8.5 using 2.5M aqueous NaOH whilst the solution was cooled to 0° C. The resulting precipitate was collected by filtration, washed with cold water (20 mL) and then dried under vacuum at 40° C. for 15 hours to give the title compound (7.1 g, 76% yield) as a light brown solid (Rf: Baseline (ethyl acetate)). 1H-NMR (300 MHz, DMSO-d6) □ 11.11 (1H, br s), 8.97 (1H, br s), 7.52 (1H, s), 6.99-6.97 (2H, m), 4.51-4.48 (1H, m), 3.33-3.31 (2H, m), 3.02-2.97 (2H, m), 2.48-2.46 (2H, m), 1.81-1.77 (2H, m); m.p.>300° C.
Reaction SMILES: [NH:1]([CH2:3][C:4]([O-:6])=[O:5])[CH3:2].[Na+].C(O)(=O)C.[N:12]#[C:13][NH2:14]>CO>[O:5]=[C:4]([CH2:3][N:1]([C:13](=[NH:12])[NH2:14])[CH3:2])[OH:6]
Reactant: CNCC(=O)[O-]
Reactant: N#CN
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(CC(=O)O)C(=N)N
Temperature: 15 °C

Procedure:
674.5 g (2.43 moles) of 40% by weight aqueous sodium sarcosinate solution were taken and a pH value of 8.5 adjusted at 70° C. with 99% by weight acetic acid. After the addition of 500 ml methanol, 491.1 g (2.92 moles) of a 25% by weight aqueous cyanamide solution were added thereto with vigorous stirring at reflux temperature in the course of 2 hours. After ending of the addition of the cyanamide solution, the reaction mixture was further stirred for 2 hours under reflux while stirring. After cooling to 15° C., the crystalline precipitate was filtered off with suction, washed twice with, in each case, 250 ml of water and subsequently recrystallised from water. After drying in a vacuum drying cabinet at 80° C. and 15 mbar pressure, there were obtained 176.7 g (48.8% by weight) of anhydrous creatine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[C:28]([F:38])=[CH:29][C:30]([F:37])=[C:31]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:32]=1>>[F:37][C:30]1[CH:29]=[C:28]([F:38])[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:32][C:31]=1[S:33]([NH2:36])(=[O:34])=[O:35]
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1cc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 5-bromo-2,4-difluorobenzenesulphonamide (245 mg, 0.9 mmol) according to general procedure II. Obtained as a yellow solid (230 mg, 42%). MS (ISP) 614.3 [(M+H)+]; mp 281-284° C.
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11][CH2:12][CH:13]([C:20]2[N:21]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[N:22]=[C:23]3[CH2:27][CH2:26][CH2:25][C:24]=23)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:6]([CH3:35])[CH:5]=1.[OH-].[Li+]>C1COCC1.CO>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([N:21]2[C:20]([CH:13]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:12][O:11][C:7]3[C:8]([CH3:10])=[CH:9][C:4]([C:3]([OH:36])=[O:2])=[CH:5][C:6]=3[CH3:35])=[C:24]3[CH2:25][CH2:26][CH2:27][C:23]3=[N:22]2)=[CH:29][CH:30]=1
Reactant: COC(=O)c1cc(C)c(OCC(c2c3c(nn2-c2ccc(Cl)cc2)CCC3)C2CCCCC2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(=O)O)cc(C)c1OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCC2)C1CCCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 137 %

Procedure:
To a solution of 4-{2-[2-(4-chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-2-cyclohexyl-ethoxy}-3,5-dimethyl-benzoic acid methyl ester (19 mg, 37 umol; example 1.5) in THF (0.7 ml) and MeOH (0.3 ml) was a added a 1 N aqueous lithium hydroxide solution (450 ul, 450 umol) at ambient temperature under an argon atmosphere. The reaction mixture was stirred for 14 h at ambient temperature and poured onto ice water/1 N aqueous HCl solution 1/1. The mixture was extracted two times with iPrOAc. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to obtain the title compound (25 mg; quant.) as colorless oil.
Reaction SMILES: [CH:1]([C:4]1[C:5]([N+:12]([O-:14])=[O:13])=[C:6]([C:9](O)=[O:10])[NH:7][N:8]=1)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.C[N:22](C)C=O>ClCCl>[CH:1]([C:4]1[C:5]([N+:12]([O-:14])=[O:13])=[C:6]([C:9]([NH2:22])=[O:10])[NH:7][N:8]=1)([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)c1n[nH]c(C(=O)O)c1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)c1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 5-isopropyl-4-nitro-2H-pyrazole-3-carboxylic acid (Farmaco, 46, 11, 1991, 1337-1350) (6 g, 0.03 mol) in N,N-dimethylformamide (69 μL) and dichloromethane (67 mL) was cooled to −5° C. in ice/acetone. Oxalyl chloride (11.48 g, 0.09 mol) was added over 30 minutes and the reaction mixture stirred for 1 hour, the reaction mixture was then allowed to return to room temperature for 2 hours. The reaction mixture was concentrated in vacuo and remaining solvent azeotroped with dichloromethane. The resulting solid was suspended in tetrahydrofuran (70 mL), cooled to 0° C. and 0.880 ammonia (25 mL) added. The reaction mixture was stirred for 30 minutes and then concentrated in vacuo. The resulting solid was suspended in water, filtered and dried at 70° C. under vacuum to yield the product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11]2[C:16]([O:17][CH3:18])=[CH:15][C:14]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH3:26])[CH:20]=3)=[C:13]([F:27])[CH:12]=2)=[C:6]([CH2:8][OH:9])[CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11]2[C:16]([O:17][CH3:18])=[CH:15][C:14]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH3:26])[CH:20]=3)=[C:13]([F:27])[CH:12]=2)=[C:6]([CH:7]=1)[CH:8]=[O:9]
Reactant: COc1cc(-c2ccc(Cl)c(C)c2)c(F)cc1Nc1ccc(Br)cc1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1cc(-c2ccc(Cl)c(C)c2)c(F)cc1Nc1ccc(Br)cc1C=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.8 %

Procedure:
A flask was charged with (5-bromo-2-((4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)amino)phenyl)methanol (6.56 g, 14.55 mmol) and DCM (72.8 ml). The solution was cooled to 0° C. To the solution was added Dess-Martin Periodinane (8.02 g, 18.92 mmol) as a solid in a single portion to give a red solution. The cold bath was removed and the solution was allowed to warm to rt. After 30 min, the solution was partitioned between DCM (100 mL) and sat. aq. sodium thiosulfite (30 mL) and 1 N NaOH (20 mL). The layers were separated and the aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were dried (Na2SO4) and filtered through a plug of silica. The red mother liquor was concentrated, then taken up in minimal DCM (10 mL). To the solution was added IPA (200 mL) and a brown/yellow solid precipitated, which was collected by vacuum filtration to yield 5-bromo-2-((4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)amino)benzaldehyde (2.339 g, 5.21 mmol, 35.8% yield) as brown/yellow solid. (ESI) 446.1 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:32])=[C:21]([NH:25]C(=O)OCC=C)[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.CC(O)=O.C([SnH](CCCC)CCCC)CCC>C(Cl)Cl.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>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:32])=[C:21]([CH:22]=[CH:23][CH:24]=2)[NH2:25])[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To a solution of 2-propen-1-yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamate (28 g, 59 mmol) in DCM (300 mL), HOAc (8.5 g, 141.6 mmol), Pd(PPh3)2Cl2 (0.827 g, 1.18 mmol) were added. Then tri-n-butyl tin hydride (27 g, 88.5 mmol) was added dropwise to the mixture at 0° C. The mixture was stirred at rt for 30 min. The reaction was quenched by added the saturated NaHCO3 (200 mL) slowly. The two layers were separated. The aqueous layer was extracted with DCM (300 mL×2). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was washed with petroleum ether (200 mL) to afford the title compound, which was used to the next step directly. (22.5 g, 97.8% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.35 (d, J=5.3 Hz, 1H), 7.01-7.08 (m, 1H), 6.98 (d, J=5.3 Hz, 1H), 6.85-6.92 (m, 1H), 6.79-6.85 (m, 1H), 4.05-4.12 (m, 2H), 3.79-3.86 (br, 2H), 3.51-3.59 (m, 2H), 3.23-3.34 (m, 1H), 2.07-2.15 (m, 2H), 1.89-2.01 (m, 2H).