Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C@H:16]1[CH2:21][CH2:20][C@H:19]([O:22][CH2:23][CH2:24][CH2:25][C:26](=O)[CH3:27])[CH2:18][CH2:17]1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[CH3:29][NH:30][CH3:31].[BH3-]C#N.[Na+].O>C(O)C.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[CH3:29][N:30]([CH3:31])[CH:26]([CH3:27])[CH2:25][CH2:24][CH2:23][O:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([N:2]([CH3:1])[S:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=2)(=[O:5])=[O:4])[CH2:17][CH2:18]1
Reactant: CC(=O)CCCO[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Reactant: CNC
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CCO
Solvent: O
Product: CC(CCCO[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1)N(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
70 mg (0.17 mmol) trans-N-Methyl-N-[4-(4-oxo-pentyloxy)-cyclohexyl]-4-trifluoromethyl-benzenesulfonamide were treated with 31 μM (30% in ethanol, 0.17 mmol) dimethylamine and 61 μM (0.17 mmol) tetraisopropyl orthotitanate. The solution was stirred at RT for 18 h, additional 31 μM (30% in ethanol, 0.17 mmol) dimethylamine and 61 μM (0.17 mmol) tetraisopropyl orthotitanate were added and stirring was continued for 2 h. The mixture was diluted with 1.7 ml ethanol and 7 mg (0.1 mmol) NaCNBH3 were added, and stirring was continued over night. 0.35 ml water was added and the suspension filtered and evaporated. The residue was purified by column chromatography with CH2Cl2/MeOH 9:1 to give 13.2 mg (18%) trans-N-[4-(4-Dimethylamino-pentyloxy)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide as colorless oil, MS: 451 (MH+).
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[C:3]([CH2:21][F:22])([CH2:19][F:20])[O:4][C:5]1[CH:11]=[CH:10][C:9]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])=[CH:8][C:6]=12.[OH:23][C:24]1[CH:29]=[CH:28][C:27](=[O:30])[N:26]([CH3:31])[N:25]=1.N1C=CC=CC=1>C(O)C>[F:18][C:12]([F:17])([C:9]1[CH:10]=[CH:11][C:5]2[O:4][C:3]([CH2:21][F:22])([CH2:19][F:20])[C@@H:2]([OH:1])[C@H:7]([O:23][C:24]3[CH:29]=[CH:28][C:27](=[O:30])[N:26]([CH3:31])[N:25]=3)[C:6]=2[CH:8]=1)[C:13]([F:15])([F:16])[F:14]
Reactant: Cn1nc(O)ccc1=O
Reactant: FCC1(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc2C2OC21
Solvent: CCO
Solvent: c1ccncc1
Product: Cn1nc(O[C@@H]2c3cc(C(F)(F)C(F)(F)F)ccc3OC(CF)(CF)[C@H]2O)ccc1=O
Yield: 75.4 %

Procedure:
A mixture of 0.58 g of 3,4-epoxy-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro-2H-1-benzopyran, 0.22 g of 3-hydroxy-1-methyl-1,6-dihydropyridazin-6-one, 0.16 g of pyridine and 5 ml of ethanol was refluxed for 5 hours. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 0.60 g of trans-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro-4-[(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)oxy]-2H-1-benzopyran-3-ol represented by the following formula having a melting point of 189°-191° C. in Example 20.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]3)=[CH:17][CH:16]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc3c(c2)CCCC3=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Hydroxy-1-tetralone (52.1)(3.24 g, 20 mmol) and 4-methoxybenzyl chloride (52.2) (3.13 g, 20 mmol) were dissolved in DMF (20 mL). Cs2CO3 (7.17 g, 22 mmol) was added to the mixture, and the resulting mixture was stirred overnight at ambient temperature. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with saturated brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was used without further purification for the next step. MS ESI (pos.) m/e: 283 (M+1)+.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:13](=[O:25])[CH2:12]2)=[S:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[C:41](OCC)(=[O:47])[C:42](OCC)=[O:43]>CN(C=O)C.CO.C1(C)C=CC=CC=1>[CH:1]1([CH2:7][N:8]2[C:42](=[O:43])[C:41]([OH:47])=[C:12]3[C:13](=[O:25])[N:14]([CH2:17][C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)[CH2:15][CH2:16][N:11]3[C:9]2=[S:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CN(C(=S)NCC2CCCCC2)CCN1Cc1ccc(F)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1c2c(O)c(=O)n(CC3CCCCC3)c(=S)n2CCN1Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
N-(Cyclohexylmethyl)-4-(4-fluorobenzyl)-3-oxopiperazine-1-carbothioamide (239 mg, 0.66 mmol) was azeotroped with anhydrous toluene and dissolved in anhydrous DMF (2 mL). The solution was cooled to 0° C., and a 1.0 M solution of lithium bis(trimethylsilyl)amide in THF (789 μL, 0.79 mmol) and diethyl oxalate (134 μL, 0.99 mmol) were added sequentially. After 15 min, the reaction was warmed to ambient temperature and treated once more with 1.0 M lithium bis(trimethylsilyl)amide in THF (789 μL, 0.79 mmol). The dark orange solution was stirred for 18 h. THF was removed by warming the reaction under a nitrogen stream, and the residue was diluted with MeOH. The resulting precipitate was collected by filtration and washed with MeOH to afford the title compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][OH:11])=[N:7][CH:8]=1)[CH3:2].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.[H-].[Na+].O>CN(C=O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(CCO)nc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(CCOc2ccc([N+](=O)[O-])cc2)nc1
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
To a solution of 2-(5-ethyl-2-pyridyl)ethanol (53.0 g) and 4-fluoronitrobenzene (47.0 g) in DMF (500 ml) was added portionwise under ice-cooling 60% sodium hydride in oil (16.0 g). The mixture was stirred under ice-cooling for one hour, then at room temperature for 30 minutes, poured into water and extracted with ether. The ether layer was washed with water and dried (MgSO4). The solvent was evaporated off to give 4-[2-(5-ethyl-2-pyridyl)ethoxy]nitrobenzene as crystals (62.0 g, 62.9%). Recrystallization from ether-hexane gave colorless prisms, m.p. 53°-54° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH3:7])=[O:3].[NH2:8][C:9]1[N:14]=[N:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])=[O:22])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1>>[CH2:5]([O:4][C:2](=[O:3])[NH:8][C:9]1[N:14]=[N:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:21](=[O:22])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])[CH2:19][CH2:20]2)=[CH:11][CH:10]=1)[CH2:6][CH3:7]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: CCCOC(=O)Cl
Product: CCCOC(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 7, making variations only as required to use propyl chloroformate in place of n-butyl chloroformate to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (72% yield). 1H NMR (500 MHz, CDCl3) δ 8.10, 7.73, 7.62, 7.55, 7.37, 7.04, 4.14, 3.96-4.02, 3.88-3.94, 3.61-3.66, 3.52-3.56, 3.32, 1.66-1.75, 0.98. MS (ES+) m/z 438 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]#[N:9])[CH:4]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:3]1.C1C=CC=CC=1.[CH2:25](O)[CH2:26][OH:27].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOC(C)=O>[C:13]1([S:10]([CH:4]2[CH:5]([C:8]#[N:9])[CH2:6][CH2:7][C:2]3([O:27][CH2:26][CH2:25][O:1]3)[CH2:3]2)(=[O:12])=[O:11])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OCCO
Reactant: N#CC1CCC(=O)CC1S(=O)(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: N#CC1CCC2(CC1S(=O)(=O)c1ccccc1)OCCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a pressure vessel was added (1R,2S and 1S,2R)-4-oxo-2-(phenylsulfonyl) cyclohexanecarbonitrile (100 mg, 0.380 mmol), benzene (19.0 mL), ethylene glycol (0.90 mL, 16 mmol), and p-toluenesulfonic acid monohydrate (14 mg, 0.076 mmol). The vessel was capped and the reaction mixture was heated to reflux and allowed to stir for 16 hours. The reaction mixture was allowed to cool to ambient temperature before it was diluted with EtOAc. The organic layer was washed with water (3×), brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo (23° C. water bath) to afford (7S,8R and 7R,8S)-7-(phenylsulfonyl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile as a crude residue. To the crude residue (110 mg, 0.358 mmol) was added THF (7.1 mL) and potassium tert-butoxide (137 mg, 1.22 mmol). The reaction mixture was allowed to stir at ambient temperature for 15 minutes before it was diluted with diethyl ether. The organic layer was washed with water, brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo (23° C. water bath) to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][OH:4].[S:9](Cl)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[OH-].[Na+]>O>[F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][O:4][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: OCC(F)(F)C(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC(F)(F)C(F)F)cc1
Temperature: 50 °C
Yield: 79 %

Procedure:
406 grams of (3.08 mo) 2,2,3,3-tetrafluoropropanol, 613 gm (3.22 mol) tosyl chloride, and 1200 ml water were heated to 50° C. with mechanical stirring. Sodium hydroxide (139.7 gm, 3.5 ml) in 560 ml water was added at a rate such that the temperature remained less than 65° C. After the addition was completed, the mixture was stirred at 50° C. until the pH of the aqueous phase was 6. The mixture was cooled and extracted with 1.5 liters methylene chloride. The organic layer was washed twice with 200 ml aqueous ammonia, 350 ml water, dried with magnesium sulfate, and distilled to give 697.2 gm (79%) viscous oil.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:9]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[O:11])=[CH:8][N:7]=[CH:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:12]2[CH2:2][CH2:3][C:4]3[C:9](=[CH:8][N:7]=[CH:6][CH:5]=3)[C:10]2=[O:11])=[CH:15][CH:16]=1
Reactant: COc1ccc(CNC(=O)c2cnccc2CCO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2CCc3ccncc3C2=O)cc1
Temperature: 0 °C
Yield: 91.2 %

Procedure:
4-(2-hydroxy-ethyl)-N-(4-methoxy-benzyl)-nicotinamide (2.2 g, 7.683 mmol) and triphenylphosphine (4.03 g, 15.37 mmol) were dissolved in 50 mL of anhydrous THF. The mixture, while being stirred at 0° C. under the nitrogen atmosphere, dropwisely added with diethyl azocarboxylate (1.4 mL, 9.220 mmol) and stirred for about 1 hour at room temperature. The mixture was then concentrated under reduced pressure and a silica gel column chromatography (3% MeOH/MC) was performed on the resulting residue and obtained 1.88 g (91%) of 2-(4-methoxy-benzyl)-3,4-dihydro-2H-[2,7]naphtyridine-1-on in white solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[CH:5][CH:4]=1.Br[C:19]1[CH:27]=[C:26]2[C:22]([C:23]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][C:24]=3[N:25]2[CH3:28])=[CH:21][CH:20]=1>>[CH3:28][N:25]1[C:26]2[C:22](=[CH:21][CH:20]=[C:19]([N:12]3[CH:13]=[CH:14][C:9]([C:6]4[CH:7]=[N:8][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:4][CH:5]=4)=[CH:10][C:11]3=[O:15])[CH:27]=2)[C:23]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][C:24]1=2
Reactant: O=c1cc(-c2ccc(C(F)(F)F)nc2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Yield: 44.8 %

Procedure:
4-(6-(Trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (145 mg, 0.604 mmol) and tert-butyl 7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (200 mg, 0.549 mmol) were coupled following the procedure of Example 30 (step g) to provide the title compound (129 mg, 45%) as a yellow/green solid: 1H NMR (500 MHz, CDCl3) δ 9.00 (s, 1H), 8.10 (dd, J=8.1, 2.0 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H), 7.60-7.57 (m, 2H), 7.36 (s, 1H), 7.08 (dd, J=8.3, 1.8 Hz, 1H), 6.93 (d, J=1.8 Hz, 1H), 6.49 (dd, J=7.1, 2.0 Hz, 1H), 4.66 (br m, 2H), 3.76 (br m, 2H), 3.66 (s, 3H), 2.82 (br m, 2H), 1.52 (s, 9H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](B(O)O)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.NC1C=C2C(C=CC=N2)=CC=1.[I-:25].[Cs+].II.N(OCCC(C)C)=O>COCCOC.[Cu]I>[I:25][C:8]1[CH:9]=[C:10]2[C:5]([CH:4]=[CH:3][CH:2]=[N:1]2)=[CH:6][CH:7]=1
Reactant: OB(O)c1ccc2cccnc2c1
Reactant: [I-]
Agent: [Cu]I
Agent: CC(C)CCON=O
Agent: II
Solvent: COCCOC
Product: Ic1ccc2cccnc2c1
Temperature: 60 °C

Procedure:
Quinolin-7-ylboronic acid. A mixture of 7-aminoquinoline (4.02 g, 27.9 mmol), CsI (Aldrich, 7.32 g, 28.2 mmol), iodine (Aldrich, 5.71 g, 22.5 mmol), CuI (Aldrich, 2.67 g, 14.0 mmol) and isoamyl nitrite (Aldrich, 22 mL, 19.18 g, 163.7 mmol) in 200 mL DME was heated to 60° C. After 2 h the reaction was cooled to room temperature and filtered. The filtrate was diluted with 300 mL toluene and washed consecutively with 25% NH4OH (2×100 mL), 5% Na2S2O3 (2×100 mL) and 5% NaCl (2×100 mL). The organic solution was dried over Na2SO4, evaporated onto SiO2 and purified by flash column chromatography eluting with EtOAc/Hex (0-25%) to give 7-iodoquinoline. MS (ESI, pos ion.) m/z: 256 (M+1). To a cooled (−78° C.) solution of the above 7-iodoquinoline (2.66 g, 10.4 mmol) in 20 mL THF was added 2.5M n-BuLi (5.0 mL, 12.5 mmol) drop-wise over 20 min. After an additional 20 min, B(OMe)3 (Aldrich, 3.0 mL, 26.9 mmol) was added dropwise and the reaction was warmed to room temperature. After 4 h the reaction was cooled to −78° C. and 2.5M n-BuLi (5.0 mL, 12.5 mmol) was added and the mixture allowed to warm to room temperature. After 2 h 2.5M HCl (40 mL) was added and the mixture washed with Et2O. The aqueous layer was neutralized with solid NaHCO3, extracted with 10% i-PrOH/EtOAc and the solvent removed in vacuo to give a rust colored amorphous solid. MS (ESI, pos ion). m/z: 174 (M+1).
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[O:7][C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].[OH-:18].[K+]>O1CCOCC1>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C@H:8]([OH:7])[CH2:9][C@H:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([OH:17])=[O:18])=[CH:11][CH:12]=1
Reactant: [OH-]
Reactant: CCCC[C@H]1C[C@H](c2ccc(F)cc2)OC1=O
Agent: [K+]
Solvent: C1COCCO1
Product: CCCC[C@@H](C[C@@H](O)c1ccc(F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the solution of (3S,5R)-3-butyl-5-(4-fluorophenyl)dihydrofuran-2(3H)-one (94.0 mg, 0.40 mmol) in 5 mL dioxane was added 5 mL aqueous 5% KOH at 25° C. After being stirred for 30 min at room temperature the reaction was quenched by the addition of 6 mL of 1M aqueous HCl. The mixture was extracted ethyl acetate (2×10 mL) and the combined organic layers were washed with brine (2×10 mL) before being concentrated under reduced pressure. The crude product was used directly in the next reaction without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].C(N(CC)CC)C.[F:12][C:13]([F:20])([F:19])[C:14](OCC)=[O:15]>CO>[F:12][C:13]([F:20])([F:19])[C:14]([NH:1][CH2:2][CH2:3][OH:4])=[O:15]
Reactant: NCCO
Reactant: CCOC(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(NCCO)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
2-Aminoethanol (4 g, 65.48 mmol, 1 equiv) was dissolved in 200 mL of methanol, and triethylamine (9.94 g, 98.23 mmol, 1.5 equiv) was added, followed by adding ethyl trifluoroacetate (11.16 g, 78.59 mmol, 1.2 equiv). After the reaction mixture was stirred overnight at room temperature, the solvent was evaporated, and the residue was dissolved in DI water and extracted with ethyl acetate. The crude product was purified by silica gel column chromatography using ethyl acetate as eluent. The obtained product was a white solid (9.8 g, 62.42 mmol, 95% yield). 1H-NMR (600 MHz, CDCl3): δ 2.07 (s, 1H, CF3CONHCH2CH2OH); δ 3.5 (t, 2H, CF3CONHCH2CH20H); δ 3.8 (t, 2H, CF3CONHCH2CH2OH); δ 6.9 (s, 1H, CF3CONHCH2CH2OH).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])=[CH:15][CH:16]=2)[NH:11][N:10]=1.Cl.[CH2:29]([O:32][NH2:33])[CH:30]=[CH2:31].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:29]([O:32][NH:33][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[NH:18][C:14]1[CH:13]=[C:12]2[C:17]([C:9](/[CH:8]=[CH:7]/[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:10][NH:11]2)=[CH:16][CH:15]=1)[CH:30]=[CH2:31]
Reactant: O=C(O)c1ccccc1Nc1ccc2c(C=Cc3ccccn3)n[nH]c2c1
Reactant: C=CCON
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCONC(=O)c1ccccc1Nc1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Reaction time: 8 h
Yield: 73.8 %

Procedure:
A solution of 2-[3-(2-Pyridin-2-yl-vinyl)-1H-indazol-6-ylamino]-benzoic acid (50.0 mg, 0.084 mmol), O-allyl-hydroxylamine hydrochloride (18.3 mg, 0.17 mmol), triethylamine(58 μl, 0.42 mmol), dissolved in DMF (0.8 mL), was treated with HATU (48 mg, 0.13 mmol). The mixture was stirred overnight, then purified by reverse phase HPLC yielding 25.5 mg (74%) of the title compound as a yellow solid. 1H NMR (DMSO-d6): δ 9.28 (1H, s), 8.67 (2H, d, J=3.4), 8.05 (4H, m), 7.48 (5H, m), 7.23 (1H, s), 7.04 (1H, d, J=7.6 Hz), 6.91 (1H, m), 3.69 (3H, s). ESIMS (M+H+): 386.1.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][NH:5][C:6]1[CH:27]=[CH:26][C:9]2[C:10]3[N:14]([CH2:15][CH2:16][O:17][C:8]=2[CH:7]=1)[CH:13]=[C:12]([C:18]1[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=1)[N:11]=3.O.[OH-].[Li+:31]>O1CCOCC1.O>[Li+:31].[CH:23]([N:19]1[C:18]([C:12]2[N:11]=[C:10]3[N:14]([CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([NH:5][CH2:4][C:3]([O-:28])=[O:2])[CH:27]=[CH:26][C:9]=43)[CH:13]=2)=[N:22][CH:21]=[N:20]1)([CH3:25])[CH3:24]
Reactant: COC(=O)CNc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(NCC(=O)[O-])cc1OCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.8 %

Procedure:
To a solution of [2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino]-acetic acid methyl ester (407 mg, 0.43 mmol) in dioxane (1 mL) and water (1 mL) was added lithium hydroxide monohydrate (36 mg, 0.86 mmol) and the reaction mixture stirred at RT for 18 h. Water was added and the reaction mixture extracted with DCM. The aqueous phase was filtered and concentrated in vacuo to give [2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino]-acetic acid lithium salt (130 mg, 81%). LCMS: RT=2.30 min, [M+H]+=369.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Cl:15][CH2:16][C:17]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:18]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-amino-pyridine (1.0 g) in dry dichloromethane (10.6 mL) under nitrogen at 0° C. was treated with triethylamine (1.63 mL) followed by slow addition of chloroacetyl chloride (0.93 mL). The reaction mixture was allowed to warm up to room temperature. After 2 hours, the mixture was partitioned between dichloromethane and water. The phases were separated and the aqueous layer was extracted with dichloromethane (×2). The combined organic layers were washed with brine, dried over magnesium sulphate, filtered and concentrated to give the crude product which was purified by silica gel chromatography eluting with 0-30% ethyl acetate/cyclohexane to give the title compound (1.43 g) as a pink solid. Further purification was achieved by trituration with 40-60 petroleum ether to give 1.15 g of the desired product. Crystallisation of a 0.94 g portion of the material from refluxing acetonitrile (2.4 mL) gave the sub-titled compound as a pink solid (0.73 g).
Reaction SMILES: FC1C=C(S(C)(=O)=O)C=CC=1OC1N=CN=C2N(C3CCC(C4ON=C(C(C)C)N=4)CC3)N=CC=12.[CH:36]([O:39][C:40]([N:42]1[CH2:47][CH2:46][CH:45]([N:48]2[C:52]3=[N:53][CH:54]=[N:55][C:56](Cl)=[C:51]3[CH:50]=[N:49]2)[CH2:44][CH2:43]1)=[O:41])([CH3:38])[CH3:37].[F:58][C:59]1[CH:60]=[C:61]([OH:69])[CH:62]=[CH:63][C:64]=1[S:65]([CH3:68])(=[O:67])=[O:66]>CN(C)C=O>[CH:36]([O:39][C:40]([N:42]1[CH2:47][CH2:46][CH:45]([N:48]2[C:52]3=[N:53][CH:54]=[N:55][C:56]([O:69][C:61]4[CH:62]=[CH:63][C:64]([S:65]([CH3:68])(=[O:67])=[O:66])=[C:59]([F:58])[CH:60]=4)=[C:51]3[CH:50]=[N:49]2)[CH2:44][CH2:43]1)=[O:41])([CH3:38])[CH3:37]
Reactant: CC(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: CS(=O)(=O)c1ccc(O)cc1F
Agent: CC(C)c1noc(C2CCC(n3ncc4c(Oc5ccc(S(C)(=O)=O)cc5F)ncnc43)CC2)n1
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)c(F)c4)ncnc32)CC1
Yield: 40 %

Procedure:
4-[4-(3-Fluoro-4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl ester was prepared using the procedure described above for the preparation of 4-(2-fluoro-4-methanesulfonyl-phenoxy)-1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidine (Example 129) by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid isopropyl ester (Intermediate 20) with 3-fluoro-4-methanesulfonyl-phenol (Intermediate 2) in dimethylformamide. The product was purified by flash chromatography, eluting with 5% methanol/dichloromethane to give 4-[4-(3-fluoro-4-methanesulfonyl-phenoxy)pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl ester (70 mg, 40%) as a white solid. Mass spectrum (ES) MH+=478.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[NH:10][CH:9]=1)=[O:7])[CH3:4].[CH3:18]I.O>CN(C)C=O>[CH2:3]([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[N:10]([CH3:18])[CH:9]=1)=[O:7])[CH3:4]
Reactant: CI
Reactant: CCOC(=O)c1c[nH]c2ccc(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(C)c2ccc(Br)cc12
Reaction time: 0.5 h

Procedure:
Sodium hydride (537 mg) was added to a solution of 5-bromo-1H-indole-3-carboxylic acid ethyl ester (3.00 g) in N,N-dimethylformamide (22 ml) at room temperature, and stirred at the same temperature for 0.5 hour. Methyl iodide (2.1 ml) was added and the mixture was stirred at the same temperature for two hours. After completion of the reaction, water was added and the precipitated solid was collected by filtration. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 5-bromo-1-methyl-1H-indole-3-carboxylic acid ethyl ester (3.10 g) as a white solid.