Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[C:3]1([C:9]([F:12])([F:11])[F:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>O>[Br:1][C:5]1[CH:4]=[C:3]([C:9]([F:12])([F:11])[F:10])[CH:8]=[CH:7][CH:6]=1
Reactant: FC(F)(F)c1ccccc1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1cccc(Br)c1
Reaction time: 0.25 h

Procedure:
3280 g of bromine are added to a mixture of 6046 g benzotrifluoride, 68 g FeCl3 and 2 g SiO2 at about 20° C. within ca. 2 hours. The reaction temperature is then slowly rised within ca. 7 hours to ca 40° C., 300 g water and 130 g Na2S2O3 are added and stirred for ca. 15 minutes. The phases are separated and the organic phase is destilled resulting in 4160 g bromo-benzotrifluoride (isomeric ratio 3:4=96:4) and 3290 g benzotrifluoride which is recycled.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](Cl)=[O:30])=[CH:24][CH:23]=1>>[CH2:13]([S:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:20])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)[N:11]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nn1nc(SCc2ccccc2)c2ccccc2c1=O
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(SCc2ccccc2)c2ccccc2c1=O

Procedure:
The product from Example 212B and (4-chlorophenyl)acetyl chloride were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.69 (s, 1H), 8.32 (dd, J=8.1, 1.3 Hz, 1H), 7.90-8.01 (m, 3H), 7.37-7.43 (m, 6H), 7.23-7.26 (m, 3H), 4.32 (s, 2H), 3.72 (s, 2H); MS (DCI+) M/Z 453 (M+NH4)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.[F:22][C:23]1[CH:24]=[C:25]([S:29]([O-:31])=[O:30])[CH:26]=[CH:27][CH:28]=1.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1>[F:22][C:23]1[CH:24]=[C:25]([S:29]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][C:13]4[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=4[C:6]=3[CH:7]=2)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1
Reactant: O=S([O-])c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(Br)cc3c2C1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)c4cccc(F)c4)cc3c2C1
Temperature: 120 °C
Yield: 36.8 %

Procedure:
A mixture of product of step B (300 mg, 0.85 mmol), sodium 3-fluorobenzenesulfinate (186 mg, 1.02 mmol), di-palladium-tris(dibenzylideneacetone) (78 mg, 0.08 mmol), cesium carbonate (416 mg, 1.28 mmol) and xantphos (99 mg, 0.17 mmol) was suspended in anhydrous toluene (4.5 mL). The reaction flask was purged with argon, sealed and heated to 120° C. for 14 h. The reaction mixture was cooled to ambient temperature, diluted with dichloromethane and filtered through a celite bed. The filtrate was concentrated in vacuo to give the crude product which was purified by flash column chromatography (SiO2, 3:2 hexanes/ethyl acetate) providing tert-butyl 8-(3-fluorophenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (135 mg, 37%) as a pale yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.08 (s, 1H), 7.83 (dd, J=8.7, 1.8 Hz, 1H), 7.77-7.72 (m, 1H), 7.65 (dt, J=7.8, 2.1 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.51-7.44 (m, 1H), 7.25-7.20 (m, 1H), 4.58 (s, 2H), 3.84 (t, J=5.4 Hz, 2H), 2.91-2.84 (m, 2H), 1.55 (s, 9H).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1.[Cl-].[Ca+2].[Cl-]>C(O)C.[Fe]>[NH2:10][C:8]1[CH:7]=[CH:6][C:5]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=2)=[C:4]([CH:9]=1)[CH2:3][N:2]([CH3:24])[CH3:1]
Reactant: CN(C)Cc1cc([N+](=O)[O-])ccc1Oc1ccc(C(F)(F)F)cc1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: CN(C)Cc1cc(N)ccc1Oc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 81.7 %

Procedure:
A mixture of the nitro compound of Example 21 (400 mg, 1.18 mmol), iron powder (591 mg, 10.6 mmol) and calcium chloride (65 mg, 0.59 mmol) in 85% aqueous ethanol (15 mL) was heated at reflux for 18 h. The reaction mixture was cooled to room temperature and filtered through Celite®, washing thoroughly with ethanol and then ethyl acetate. The solvent was removed in vacuo and the residue was purified by flash chromatography [SiO2; DCM/ MeOH/ 880 NH3 (95:5:0.5)] to give the desired aniline compound (299 mg, 82%) as a beige solid; δH(CDCI3, 300 MHz) 2.20 (6 H, s), 3.27 (2 H, s), 3.63 (2 H, brs), 6.60 (1 H, dd), 6.80 (1 H, d), 6.87 (1 H, d), 6.90 (2 H, d), 7.50 (2 H, d); MS m/z (TS+) 310 (MH+).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:17])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:16])(=[O:15])[NH:11][CH2:12][CH2:13]O)=[CH:6][CH:5]=1.C(C1C=CC(S(Cl)(=O)=O)=CC=1)#N.[C:30]([O:34][C:35](=[O:40])[NH:36]CCN)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35](=[O:40])[NH:36][CH2:13][CH2:12][NH:11][S:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3](=[NH:17])[NH:2][OH:1])=[CH:5][CH:6]=1)(=[O:16])=[O:15])([CH3:33])([CH3:32])[CH3:31]
Reactant: N=C(NO)c1ccc(S(=O)(=O)NCCO)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: N#Cc1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1ccc(C(=N)NO)cc1

Procedure:
The title compound is prepared in analogy to N-hydroxy-4-(2-hydroxy-ethylsulfamoyl)-benzamidine starting from 4-cyano-benzenesulfonyl chloride and (2-amino-ethyl)-carbamic acid tert-butyl ester; LC-MS: tR=0.40 min; [M+1]+=359.09; 1H NMR (D6-DMSO): δ1.35 (s, 9H), 2.73-2.81 (m, 2H), 2.92-3.00 (m, 2H), 5.96 (s, 2H), 6.78 (t br, J=5.5 Hz, 1H), 7.69 (t br, J=6.0 Hz, 1H), 7.75-7.79 (m, 2H), 7.86-7.90 (m, 2H), 9.92 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])(=[O:29])=[O:28].[CH3:38][Zn]C.C1(C)C=CC=CC=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:38])[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])(=[O:29])=[O:28]
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1cc(F)ccc1F
Reactant: C[Zn]C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2Cl)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 13.1 %

Procedure:
A solution of N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide (0.15 g, 0.26 mmol) in 1,4-dioxane (3 mL) with PdCl2(dppf) (0.047 g, 0.064 mmol) was degassed for 5 min. To this mixture was added 2.0 M dimethylzinc in toluene (0.39 mL, 0.77 mmol). The reaction mixture was heated to 80° C. After 2 h, the reaction was quenched slowly with MeOH (15 mL) and then was further diluted with DCM (50 mL), filtered through a nylon membrane and evaporated to a crude yellow residue. The residue was purified by silica gel chromatography eluting 0-100% EtOAC/hexanes, followed by 10% EtOH/EtOAc. The resulting solid was dissolved in DCM (10 mL) and hexanes (20 mL) added to afford the title compound as a yellow solid (0.02 g; 13.1% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.72 (s, 1H), 8.26 (d, J=5.6 Hz, 1H), 7.51-7.60 (m, 2H), 7.40-7.50 (m, 3H), 7.32-7.39 (m, 1H), 6.07 (d, J=5.5 Hz, 1H), 3.71 (t, J=4.8 Hz, 4H), 3.48-3.53 (m, 4H) *Note: The 2-Me group is submerged under the water peak at 2.5 ppm. MS (ESI) 564.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][C@H:8]2[CH2:11][C@H:10]([CH2:12][OH:13])[CH2:9]2)=[CH:5][CH:4]=1.C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][C@H:8]2[CH2:11][C@H:10]([CH:12]=[O:13])[CH2:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(O[C@H]2C[C@H](CO)C2)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: COc1ccc(O[C@H]2C[C@H](C=O)C2)cc1
Yield: 62.1 %

Procedure:
To a stirred mixture of {trans-3-(4-methoxyphenoxy)cyclobutyl}methanol (19.8 g, 95.3 mmol), N-methylmorpholine N-oxide (16.7 g, 143 mmol) and powdered 4A molecular sieves (48 g) in methylene chloride (190 ml) was added solid tetrapropylammonium perruthenate (1.67 g, 4.80 mmol) at room temperature under argon atmosphere. On completion, the mixture was filtered through a pad of silica, eluting with methylene chloride (500 ml). The filtrate was evaporated and the residue purified by silica-gel column chromatography {SiO2, 500 g; hexane/ethyl acetate (3/1)} to afford 12.2 g (62%) of trans-3-(4-methoxyphenoxy)cyclobutanecarbaldehyde as white solids: 1H NMR δ9.88 (s, 1H), 6.88-6.65 (m, 4H), 4.75-4.58 (m, 1H), 3.76 (s, 3H), 3.31-3.15 (m, 1H), 2.82-2.61 (m, 2H), 2.54-2.25 (m, 3H).
Reaction SMILES: [O:1]=[C:2]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])/[CH:3]=[CH:4]/[C:5]1[O:6][CH:7]=[CH:8][C:9](=[O:22])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C([BH-](CC)CC)C.[Li+]>O1CCCC1>[OH:1][CH:2]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])/[CH:3]=[CH:4]/[C:5]1[O:6][CH:7]=[CH:8][C:9](=[O:22])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCCCCC(=O)/C=C/c1occc(=O)c1OCCCCCC(=O)OCC
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCC(O)/C=C/c1occc(=O)c1OCCCCCC(=O)OCC
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a solution, cooled under nitrogen to -78°, of 0.200 g (0.53 mmol) of 2-(3-oxo-trans-1-octenyl)-3-(5-carboethoxypentyloxy)-4-pyrone in 2 ml of tetrahydrofuran was added dropwise keeping the internal temperature at -70° to -75°, 0.53 ml (0.53 mmole) of lithium triethylborohydride. After being stirred for an additional 30 min the cold reaction was quenched by the addition of 0.5 ml of 40% aqueous acetic acid and then partially concentrated under reduced pressure. The residue was dissolved in methylene chloride and washed successively with aqueous sodium bicarbonate and brine solution. The organic solution was dried over magnesium sulfate and evaporated to give an oil. Chromatographic purification on silica gel eluting with ether furnished 0.131 g (65%) of 2-[(3RS)-3-hydroxy-trans-1-octenyl]-3-(5-carboethoxypentyloxy)-4-pyrone. NMR (CDCl3, 100 M Hz): δ0.90 (3H, t, J = 4.5 Hz), 2.33 (2 H, t, J = 6 Hz), 4.13 (4H, m), 4.35 (1H, m).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([C:12]1[CH:17]=[CH:16][C:15]([C@H:18]2[CH2:23][CH2:22][C@H:21]([NH:24][CH3:25])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)[CH2:9][NH:10][CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>>[C:1]([O:5][C:6]([CH:8]([C:12]1[CH:17]=[CH:16][C:15]([C@H:18]2[CH2:23][CH2:22][C@H:21]([N:24]([C:31](=[O:32])[C:30]3[CH:34]=[CH:35][C:27]([Cl:26])=[CH:28][CH:29]=3)[CH3:25])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)[CH2:9][NH:10][CH3:11])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CNCC(C(=O)OC(C)(C)C)c1ccc([C@H]2CC[C@H](NC)CC2)cc1
Product: CNCC(C(=O)OC(C)(C)C)c1ccc([C@H]2CC[C@H](N(C)C(=O)c3ccc(Cl)cc3)CC2)cc1

Procedure:
from trans-4-[4-(1-tert.butoxycarbonyl-methylaminoethyl)-phenyl]-N-methylcyclohexylamine and 4-chlorobenzoylchloride. Melting point: 172°-174° C.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]([C:23]([NH:25][CH2:26][CH:27]([OH:37])[CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:24])[CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])C1C=CC=CC=1>C(O)C.[Pd]>[C:19]([O:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][C@@H:11]([C:23]([NH:25][CH2:26][CH:27]([OH:37])[CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:24])[NH2:10])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(O)CNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCC[C@H](N)C(=O)NCC(O)CNC(=O)OC(C)(C)C

Procedure:
Preparation takes place in analogy to Example 81A from 412 mg (0.76 mmol) of benzyl{(1S)-4-[(tert-butoxycarbonyl)amino]-1-[({3-[(tert-butoxycarbonyl)amino]-2-hydroxypropyl}amino)carbonyl]butyl}carbamate (Example 80A) in 50 ml of ethanol with the addition of 41 mg of palladium on activated carbon (10%). The product is reacted without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[N:7]([CH2:9][CH2:10][O:11][NH2:12])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.FC1C([O:30][C:31](=O)[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[C:33]=2[NH:40][C:41]2[CH:46]=[CH:45][C:44]([I:47])=[CH:43][C:42]=2[CH3:48])=C(F)C(F)=C(F)C=1F>CN(C)C=O>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:9][CH2:10][O:11][NH:12][C:31]([C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[C:33]=1[NH:40][C:41]1[CH:46]=[CH:45][C:44]([I:47])=[CH:43][C:42]=1[CH3:48])=[O:30])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCON)C(=O)OC(C)(C)C
Reactant: Cc1cc(I)ccc1Nc1c(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc(F)c1F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(I)ccc1Nc1c(C(=O)NOCCN(C)C(=O)OC(C)(C)C)ccc(F)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.6 %

Procedure:
To a solution of (2-aminooxy-ethyl)-methyl-carbamic acid tert-butyl ester (0.63 g, 3.31 mmol) and diisopropylethylamine (0.6 mL, 3.44 mmol) in dimethylformamide (10 mL) was added 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid pentafluorophenyl ester (1.66 g, 2.99 mmol). The resultant reaction mixture was stirred 5 h at ambient temperature and concentrated under reduced pressure. The residue was diluted with ether (100 mL), washed with water (2×25 mL) and brine (2×25 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography. Elution with dichloromethane afforded [2-({1-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-methanoyl}-aminooxy)-ethyl]-methyl-carbamic acid tert-butyl ester (1.05 g, 62%) as a white foam: 1 H NMR (400 MHz, DMSO-d6) δ 11.85 and 11.80 (br s, 1 H), 8.49 (br s, 1 H), 7.50 (s, 1 H), 7.39 (m, 1H), 7.35 (d, J=8.3 Hz, 1 H), 7.14 (m, 1 H), 6.46 (dd, J=7.8, 5.9 Hz, 1 H), 3.85 (br s, 2 H), 3.35 (br s, 2 H), 2.79 (br s, 3 H), 2.21 (s, 3 H), 1.36 and 1.33 (s, 9 H); 19F NMR (376 MHz, DMSO-d6) δ −132.9, −143.3 (d, J=17.7 Hz); MS (APCI+)=562.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:11](=[C:12]([CH3:15])[C:13]=1[CH3:14])[O:10][CH2:9][C:6]1([CH2:8][CH2:7]1)[C:5]2=O.Cl.[CH3:18][O:19][NH2:20]>N1C=CC=CC=1>[CH3:18][O:19][N:20]=[C:5]1[C:6]2([CH2:8][CH2:7]2)[CH2:9][O:10][C:11]2[C:4]1=[CH:3][C:2]([OH:1])=[C:13]([CH3:14])[C:12]=2[CH3:15]
Reactant: Cc1c(O)cc2c(c1C)OCC1(CC1)C2=O
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1c2cc(O)c(C)c(C)c2OCC12CC2
Temperature: 200 °C
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
A solution of 6-hydroxy-7,8-dimethyl-4H-spiro[chromene-3, 1′-cyclopropan]-4-one (10 mg), prepared as described above, methoxyamine hydrochloride (110 mg) in pyridine (3 mL) was stirred in a microwave reaction tube (200° C., 30 min). After cooling down, the mixture was partitioned between water and ethylacetate, and the organic layer was washed with dil. HCl, dried, and evaporated. The residue was purified by silica gel column eluting with 15% EtOAc in hexane to give a 3.6 mg of 6-hydroxy-7,8-dimethylspiro[chroman-3,1′-cyclopropan]-4-one O-methyl oxime.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C@H:8]([CH3:12])[CH2:9][C:10]#[N:11])[CH2:4][CH2:3]1.[F:13][C:14]([F:24])([F:23])[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>>[F:13][C:14]([F:23])([F:24])[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:20][CH:2]2[CH2:7][CH2:6][N:5]([C@H:8]([CH3:12])[CH2:9][C:10]#[N:11])[CH2:4][CH2:3]2)=[CH:21][CH:22]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Product: C[C@H](CC#N)N1CCC(Nc2ccc(OC(F)(F)F)cc2)CC1
Yield: 113 %

Procedure:
Using general procedure A, (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (2.0 g, 12 mmol) and 4-(trifluoromethoxy)aniline (1.34 mL, 10.0 mmol) gave (R)-3-[4-(4-trifluoromethoxy-phenylamino)-piperidin-1-yl]-butyronitrile as a pale yellow solid (3.7 g, 94%).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[C:9]([F:12])[CH:10]=2)[C:5](=[O:14])[CH:4]=[C:3]1C(O)=O.[BH4-].[Na+]>CO>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[C:9]([F:12])[CH:10]=2)[C:5](=[O:14])[CH2:4][CH2:3]1
Reactant: Cn1c(C(=O)O)cc(=O)c2cc(F)c(F)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCC(=O)c2cc(F)c(F)cc21
Temperature: 0 °C
Yield: 62.4 %

Procedure:
1-Methyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline carboxylic acid(7 g) was added to methyl alcohol(800 ml), and stirred at 0° C. After sodium borohydride(4.3 g) and p-toluene sulfonic acid(cat.amount) were added thereto, the reaction mixture was refuluxed for an hour, and the organic solvent was removed under reduced pressure. To the residue was added chloroform(500 ml), and it was washed twice with water (200 ml). The separated organic layer was dehydrated, and concentrated. The residue was solidified with pet. ether, and dried to give the bright-yellow-above-indicated compound(3.6 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.ON1C2C=CC=CC=2N=N1.[CH3:28][NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:28][NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:15][C:14]2[CH:16]=[CH:17][C:11]([C:9]3[N:10]=[C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]4[CH:8]=3)=[CH:12][CH:13]=2)=[O:35])=[CH:32][CH:31]=1
Reactant: CNc1ccc(C(=O)O)cc1
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)cn2c1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNc1ccc(C(=O)Nc2ccc(-c3cn4cc(C)ccc4n3)cc2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 33.2 %

Procedure:
To a stirred solution of 4-(6-methylimidazo[1,2-a]pyridin-2-yl)aniline (0.10 g, 0.448 mmol), 1-hydroxybenzotriazole (0.06 g, 0.448 mmol), 4-methylaminobenzoic acid (0.068 g, 0.448 mmol) and triethylamine (62 μl, 0.045 g, 0.448 mmol) in dry DMF (5 ml) at 0° C. was added 1-ethyl-3-[3-(dimethylaminopropyl]-carbodiimide hydrochloride (0.086 g, 0.448 mmol) under an atmosphere or argon. After 10 min the cooling bath was removed and the reaction mixture was stirred at room temperature for 4 d. The reaction mixture was then added to water (150 ml) with stirring and the precipitate was collected by filtration. Purification by flash chromatography (25:1 DCM/MeOH) gave the title compound (0.053 g, 33%) as an almost colourless solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:16][CH2:17][C:18](=[O:20])[CH3:19])([CH2:13][CH2:14][CH3:15])[C:8]2=O)=[CH:4][C:3]=1[CH2:21][C:22]([OH:24])=[O:23].Cl>[OH-].[Na+].O>[Cl:11][C:10]1[C:2]([Cl:1])=[C:3]([CH2:21][C:22]([OH:24])=[O:23])[CH:4]=[C:5]2[C:9]=1[C:8]1[C:7]([CH2:13][CH2:14][CH3:15])([CH2:6]2)[CH2:16][CH2:17][C:18](=[O:20])[CH:19]=1
Reactant: CCCC1(CCC(C)=O)Cc2cc(CC(=O)O)c(Cl)c(Cl)c2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCC12CCC(=O)C=C1c1c(cc(CC(=O)O)c(Cl)c1Cl)C2

Procedure:
[6,7-Dichloro-2,3-dihydro-1-oxo-2-(3-oxobutyl)-2-propyl-1H-inden-5-yl]acetic acid (3.0 g, 0.00808 mole) was dissolved in 25 ml 1N sodium hydroxide and 6 ml water, stirred at room temperature for 70 hours and then the reaction was diluted with water and acidified with hydrochloric acid. The product was extracted with methylene chloride, the organic extracts were washed with water, dried over MgSO4, concentrated under vacuum and the residue recrystallized from acetonitrile to obtain the product, mp 206°-8° C.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])=[C:6]([Cl:18])[N:5]=[CH:4][N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:29][C:2]2[C:7]([O:8][C:9]3[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=3[O:16][CH3:17])=[C:6]([Cl:18])[N:5]=[CH:4][N:3]=2)(=[O:27])=[O:28])=[CH:24][CH:25]=1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: COc1ccc(F)cc1Oc1c(Cl)ncnc1Cl
Product: COc1ccc(F)cc1Oc1c(Cl)ncnc1NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The 4-chloro-N-[6-chloro-5-(5-fluoro-2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulfonamide (m.p. 169°-171° C.) was prepared from 4,6-dichloro-5-(5-fluoro-2-methoxy-phenoxy)-pyrimidine and 4-chlorobenzenesulfonamide K.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:31])=[N:4][CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH3:30])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1.FC1C=CC(C2N=C(C3CCNCC3)N(C[CH2:45][N:46]3[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]3)C=2)=CC=1C(F)(F)F>>[Br:1][C:2]1[C:3]([NH2:31])=[N:4][CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:30][CH2:45][N:46]3[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]3)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:28])([F:29])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1
Reactant: Fc1ccc(-c2cn(CCN3CCCCC3)c(C3CCNCC3)n2)cc1C(F)(F)F
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2Br)CC1
Product: Nc1ncnc(N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3CCN3CCCCC3)CC2)c1Br

Procedure:
The title compound was prepared in an analogous manner as 5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 1-(2-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(piperidin-4-yl)-1H-imidazol-1-yl)ethyl)piperidine instead of 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS: (M+1=596, obsd.=596).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[S:19][N:18]=[C:17]([CH3:20])[C:16]=2Br)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.C([Sn](CCCC)(CCCC)[C:27]1[N:28]([CH3:32])[CH:29]=[N:30][CH:31]=1)CCC>CN(C=O)C>[NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[S:19][N:18]=[C:17]([CH3:20])[C:16]=2[C:27]2[N:28]([CH3:32])[CH:29]=[N:30][CH:31]=2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: Cc1nsc(NC(=O)c2c(N)nn3cc(F)cnc23)c1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Solvent: CN(C)C=O
Product: Cc1nsc(NC(=O)c2c(N)nn3cc(F)cnc23)c1-c1cncn1C
Temperature: 110 °C
Reaction time: 2 h

Procedure:
2-amino-N-(4-bromo-3-methyl-isothiazol-5-yl)-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxamide (20 mg, 0.05388 mmol), tributyl-(3-methylimidazol-4-yl)stannane (40.01 mg, 0.1078 mmol) dichloropalladium triphenylphosphane (7.566 mg, 0.01078 mmol) in DMF (2 mL) was degassed for 5 min, then heated at 110° C. After 2 h, the reaction mixture was loaded on a SCX column, washed with DCM/MeOH mixtures. The product was eluted with a 2M solution of ammonia in MeOH and the eluent was concentrated in vacuo. The residue was purified by fractionlynx to yield 2-amino-6-fluoro-N-(3-methyl-4-(1-methyl-1H-imidazol-5-yl)isothiazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a pale yellow solid. (8.09 mg, 37.4%). MS (ES+) 373.1.