Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH3:9][C:10]([CH3:14])=[CH:11][CH2:12]Br>>[CH3:9][C:10]([CH3:14])=[CH:11][CH2:12][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: Oc1ccccc1S
Reactant: CC(C)=CCBr
Product: CC(C)=CCSc1ccccc1O
Yield: 99 %

Procedure:
This compound was prepared in 99% yield from 2-mercaptophenol and 3-methyl-2-butenylbromide according to the general procedure for 16p in Example VII. Colorless Oil; 1H NMR (CDCl3): δ 1.29 (s, 3H), 1.66 (s, 3H), 3.30 (d, J=8.00 Hz, 2H), 5.21-5.26 (m, 1H), 6.82 (s, 1H), 6.84 (dt, J=1.35 Hz, J=7.40 Hz, 1H), 6.96 (dd, J=1.10 Hz, J=8.25 Hz, 1H), 7.26 (dt, J=1.65 Hz, J=7.70 Hz, 1H), 7.43 (dd, J=1.95 Hz, J=7.70 Hz, 1H); 13C NMR (CDCl3): δ 17.25, 25.70, 34.79, 114.56, 118.66, 119.14, 120.53, 131.31, 136.87, 137.25, 157.44; HRMS (FAB): 194.07654 calcd for C11H14OS [M]+ 194.0771 (2.9 ppm, 0.6 mmu).
Reaction SMILES: Cl[C:2]1[N:25]=[C:5]2[C:6]([NH:10][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[CH3:12])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:24][N:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:11]([NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:39][C:36]3[CH:35]=[CH:34][C:33]([N:30]4[CH2:29][CH2:28][N:27]([CH3:26])[CH2:32][CH2:31]4)=[CH:38][CH:37]=3)[N:25]=2)[CH:9]=[CH:8][CH:7]=1)[CH3:12])[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: CC(Nc1cccn2nc(Cl)nc12)c1ccccc1N(C)S(C)(=O)=O
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CC(Nc1cccn2nc(Nc3ccc(N4CCN(C)CC4)cc3)nc12)c1ccccc1N(C)S(C)(=O)=O

Procedure:
197 h) N-Methyl-N-[2-(1-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-ethyl)-phenyl]-methanesulfonamide was prepared from N-{2-[1-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-ethyl]-phenyl}-N-methyl-methanesulfonamide (75.0 mg, 0.197 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (42.0 mg, 0.220 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (18.0 mg, 0.0329 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a pale yellow solid (0.008 g, 8%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.77-7.25 (m, 8H), 7.00-6.93 (m, 2H), 6.65-6.30 (m, 3H), 5.40-5.24 (m, 1H), 5.00-4.91 (m, 1H), 3.35-3.29 (m, 3H), 3.19-3.13 (m, 4H), 3.07-3.01 (m, 3H), 2.63-2.58 (m, 4H), 2.36 (s, 3H), 1.72-1.55 (m, 3H). MS=535 (MH)+.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH2:25][OH:26])=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]3)[N:13]=2)=[CH:5][CH:4]=1.[H-].[Na+].F[C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[C:34]([O:40][CH3:41])[CH:33]=1>CN(C)C=O>[CH3:41][O:40][C:34]1[CH:33]=[C:32]([O:26][CH2:25][C:11]2[S:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:27])[F:28])=[CH:4][CH:5]=3)=[N:13][C:12]=2[CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]([F:22])([F:24])[F:23])[CH2:17][CH2:16]2)[CH:39]=[CH:38][C:35]=1[C:36]#[N:37]
Reactant: OCc1sc(-c2ccc(C(F)(F)F)cc2)nc1CN1CCC(C(F)(F)F)CC1
Reactant: COc1cc(F)ccc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CN2CCC(C(F)(F)F)CC2)ccc1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To a solution of 474 mg of [2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-yl]-methanol in 2.9 mL of dimethylformamide was added 60 mg of sodium hydride. The resulting mixture was stirred for 30 minutes at 0° C. then 208 mg of 4-fluoro-2-methoxybenzonitrile was added. After stirring for 30 minutes at 0° C., the temperature was allowed to warm up to room temperature and the reaction mixture was stirred for 30 minutes. The solvent was removed under reduced pressure and dichloromethane/water was added to the residue. The organic layer was separated and the aqueous layer extracted three times with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (dichloromethane 95/methanol 5) to give 279 mg of 2-methoxy-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11](Br)[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:14]([B-](F)(F)F)=[CH2:15].[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Cl:1][C:2]1[CH:12]=[C:11]([CH:14]=[CH2:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C=C[B-](F)(F)F
Reactant: CCOC(=O)c1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C=Cc1ccc(C(=O)OCC)c(Cl)c1
Temperature: 80 °C
Yield: 68.4 %

Procedure:
To a stirred solution of ethyl 2-chloro-4-bromobenzoate (2 g, 7.63 mmol) in dimethylsulfoxide (20 mL) was added potassium vinyltrifluoroborate (3.06 g, 22.9 mmol) and potassium carbonate (3.16 g, 22.9 mmol). The reaction mixture was degassed with argon for 30 min Bistriphenylphosphine(diphenylphosphinoferrocene)palladium dichloride (0.27 g, 0.38 mmol) was added and the reaction mixture was heated to 80° C. for 1 h. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (2×50 mL), washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain the compound as brown gummy material (1.1 g, 69%): 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J=8.4 Hz, 1H), 7.46 (s, 1H), 7.33 (d, J=8.4 Hz, 1H), 6.70 (dd, J=17.6, 11.2 Hz, 1H), 5.87 (d, J=17.6 Hz, 1H), 5.42 (d, J=10.8 Hz, 1H), 4.41 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H); ESIMS m/z 211.22 ([M+H]+); IR (thin film) 1729, 886 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:32](=[O:47])[NH:33][C:34]2([C:37]3[CH:42]=[CH:41][C:40]([C:43]([O:45][CH3:46])=[O:44])=[CH:39][CH:38]=3)[CH2:36][CH2:35]2)[C:5]([N:8]2[CH2:11][CH:10]([O:12][C:13]3[CH:14]=[C:15]([N:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)[CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[N:6][CH:7]=1.FC(F)(F)C(O)=O.ClCCl>ClCCl>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:11][CH:10]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:14]=3)[CH2:9]2)=[C:4]([CH:3]=1)[C:32]([NH:33][C:34]1([C:37]2[CH:42]=[CH:41][C:40]([C:43]([O:45][CH3:46])=[O:44])=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:47]
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Oc4cccc(N5CCN(C(=O)OC(C)(C)C)CC5)c4)C3)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Oc4cccc(N5CCNCC5)c4)C3)CC2)cc1
Reaction time: 0.25 h
Yield: 95.3 %

Procedure:
To a cooled solution of tert-butyl 4-(3-((1-(5-chloro-3-((1-(4-(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)pyridin-2-yl)azetidin-3-yl)oxy)phenyl)piperazine-1-carboxylate (130 mg, 0.196 mmol) in dichloromethane (1 ml) a mixture trifluoroacetic acid/dichloromethane (3 ml/1 ml) was added and the resulting mixture stirred for 15 min. Solvents were evaporated in vacuo to afford a residue that was loaded on SPE-SCX (5 g) cartridge. Ammonia fractions after solvent evaporation afforded the title compound (D156) (105 mg)
Reaction SMILES: Br[C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(N(CC)C(C)C)(C)C.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.[CH2:65]1[CH2:70][CH2:69][CH:68]([SH:71])[CH2:67][CH2:66]1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:12][C:10]1[CH:11]=[C:2]([S:71][CH:68]2[CH2:69][CH2:70][CH2:65][CH2:66][CH2:67]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)cc(Br)c1C
Reactant: SC1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)c1cc(Cl)cc(SC2CCCCC2)c1C
Yield: 88.3 %

Procedure:
To a stirred solution of methyl 3-bromo-5-chloro-2-methylbenzoate (1.0 g, 3.79 mmol) in 1,4-dioxane was added N,N-diisopropyl ethylamine (0.98 g, 7.59 mmol). The reaction mixture was purged with argon for 20 min. then Pd(OAc)2 (0.042 g, 0.189 mmol), Xanthphos (0.22 g, 0.38 mmol) and cyclohexylthiol (0.44 g, 3.79 mmol) was added to it sequentially and again purged with argon for 10 min. The reaction mixture was then refluxed for 16 h. On completion, water was added, and the product extracted with ethyl acetate. The organic layer was dried over sodium sulphate and the product was purified by silica gel column to afford the title compound (1.0 g, 83%)
Reaction SMILES: [Li][CH2:2][CH2:3]CC.[CH:6]([C:8]1[CH:28]=[C:27]([C:29]2[C:38]3[C:33](=[CH:34][C:35]([O:39][CH3:40])=[CH:36][CH:37]=3)[O:32][C:31](=[O:41])[CH:30]=2)[CH:26]=[CH:25][C:9]=1[O:10][C:11]1[CH:12]=[C:13]([C@@:17]2([CH3:24])[O:21][C:20](=[O:22])[NH:19][C:18]2=[O:23])[CH:14]=[CH:15][CH:16]=1)=O>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1COCC1>[CH3:40][O:39][C:35]1[CH:34]=[C:33]2[C:38]([C:29]([C:27]3[CH:26]=[CH:25][C:9]([O:10][C:11]4[CH:12]=[C:13]([C@@:17]5([CH3:24])[O:21][C:20](=[O:22])[NH:19][C:18]5=[O:23])[CH:14]=[CH:15][CH:16]=4)=[C:8]([CH2:6][CH2:2][CH3:3])[CH:28]=3)=[CH:30][C:31](=[O:41])[O:32]2)=[CH:37][CH:36]=1
Reactant: [Li]CCCC
Reactant: COc1ccc2c(-c3ccc(Oc4cccc([C@@]5(C)OC(=O)NC5=O)c4)c(C=O)c3)cc(=O)oc2c1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCc1cc(-c2cc(=O)oc3cc(OC)ccc23)ccc1Oc1cccc([C@@]2(C)OC(=O)NC2=O)c1
Temperature: -75 °C
Reaction time: 18 h

Procedure:
To a suspension of ethyltriphenylphophonium bromide (0.56 g, 1.5 mmol) in THF (8 mL) cooled at −75° C. was added n-BuLi (1.6 M in hexane, 1.0 mL). To the resulting orange solution was added the product from step 2 (0.24 g, 0.50 mol) in THF (1.0 mL). The reaction mixture was gradually warmed to 25° C. and quenched with acetic acid (0.1 mL). The solvent was removed and the residue was taken up in diethyl ether and filtered through a short column of silica gel. The filtrated was concentrated and the residue was dissolved in THF-t-BuOH (1:1, v/v) (10 mL). The solution was stirred in the presence of Rh(PPh3)3Cl (40 mg) under hydrogen (45 psi) for 18 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC on a RP-18 column using 10-100% acetonitrile in water gradient solvent system modified with 0.1% trifluoroacetic acid to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C@@H:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[C:21]([F:30])[CH:20]=2)[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:9])[CH:5]=[CH:4][C:3]=1[OH:31].Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl.CCOC(C)=O>C1COCC1>[F:30][C:21]1[CH:20]=[C:19]([C@@H:11]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[NH:10][C:8]([C:6]2[N:7]=[C:2]3[NH:1][C:33](=[O:35])[O:31][C:3]3=[CH:4][CH:5]=2)=[O:9])[CH:24]=[CH:23][C:22]=1[O:25][C:26]([F:29])([F:27])[F:28]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1nc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)ccc1O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F)c1ccc2oc(=O)[nH]c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-6-amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-hydroxypicolinamide (300 mg, 0.681 mmol) in THF (10 mL) was added TEA (689.4 mg, 0.00068 mmol, S.d fine, India) and triphosgene (242 mg, 0.0008 mmol, Sigma Aldrich, India) at 0° C. The reaction mixture was stirred for 2 h at room temperature. After completion of the reaction, monitored by TLC (TLC eluent: 50% EtOAc in petroleum ether), the reaction mixture was quenched with sat'd NaHCO3 solution and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel (60-120 mesh) column chromatography eluting with 80-100% EtOAc in petroleum ether to afford the title compound as an off white solid. 1H-NMR (400 MHz, DMSO-d6): δ 12.8 (br. s., 1H), 9.46 (d, J=7.2 Hz, 1H), 8.55 (d, J=4.4 Hz, 1H), 7.83-7.77 (m, 3H), 7.57-7.49 (m, 3H), 7.33 (d, J=8.4 Hz, 1H), 6.55 (d, J=6.8 Hz, 1H). MS (ESI, positive ion) m/z: 467.2 (M+H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[O:3][C:4]1[CH:32]=[CH:31][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][NH:16][CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[O:11])=[CH:6][CH:5]=1.Cl[C:36]1[S:37][C:38]2[CH:43]=[N:42][NH:41][C:40](=[O:44])[C:39]=2[N:45]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[F:34][C:2]([F:1])([F:33])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:36]3[S:37][C:38]4[CH:43]=[N:42][NH:41][C:40](=[O:44])[C:39]=4[N:45]=3)[CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[O:11])=[CH:31][CH:32]=1
Reactant: O=c1[nH]ncc2sc(Cl)nc12
Reactant: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CNCCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3c(=O)[nH]ncc3s2)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
To a mixture of the compound (87 mg) obtained in Example 983, Step 2 and the compound (32 mg) obtained in Step 5 in isopropanol (0.9 ml) was added N,N-diisopropylethylamine (30 μl) at room temperature. After stirring overnight at room temperature, and the mixture was stirred with heating under reflux for 5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by thin layer silica gel chromatography (methanol:chloroform=5:95) to give the title compound (84 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[N:13]=1.[H-].[Na+].Br[CH2:27]/[CH:28]=[CH:29]/[C:30]([O:32][CH3:33])=[O:31]>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]1[NH:10][C:11]([CH2:27]/[CH:28]=[CH:29]/[C:30]([O:32][CH3:33])=[O:31])=[C:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[N:13]=1
Reactant: COC(=O)/C=C/CBr
Reactant: O=C(OCc1ccccc1)c1c[nH]c(Cc2ccccc2Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)/C=C/Cc1[nH]c(Cc2ccccc2Br)nc1C(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
To a stirring solution of phenylmethyl 2-[(2-bromophenyl)methyl]imidazole-4-carboxylate in dimethyl foramide (0.1M) was added sodium hydride (1.2 eq) The reaction was allowed to stir for 10 mins. followed by addition of methyl 4-bromocrotonate continued stirring for 18 hr. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was extracted with 10% hydrochloric acid and the aqueous layer was neutralized with saturated sodium carbonate. The aqueous layer eas extracted with ethyl acetate and dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (50% EtOAc/Hexane). EI-MS m/z 406/408 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].BrC1C=C(O)C=CC=1.[C:18]1([CH:24]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27](=[O:34])[C:26]2=[O:35])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.FC(F)(F)C1OC(CN2C3C(=CC=CC=3)C(=O)C2=O)=CC=1>>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:27]2([OH:34])[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:25]([CH:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:26]2=[O:35])=[C:4]([OH:9])[CH:3]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: Oc1ccc(F)c(F)c1
Agent: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Agent: Oc1cccc(Br)c1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc(F)c(F)cc1O

Procedure:
Following the procedure as described in PREPARATION 2A and making non-critical variations using 3,4-difluorophenol to replace 3-bromophenol, and 1-(diphenylmethyl)-1H-indole-2,3-dione to replace 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione, 3-(4,5-difluoro-2-hydroxyphenyl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one was obtained (61%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ9.23 (br s, 1H), 7.47-7.44 (m, 1H), 7.35-7.21 (m, 9H), 7.18-7.11 (m, 2H), 6.90 (s, 1H), 6.83 (dd, J=11.2, 6.9 Hz, 1H), 6.67 (dd, J=11.2, 8.7 Hz, 1H), 6.56-6.51 (m, 1H), 4.13 (br s, 1H); MS (ES+) m/z 426.2 (M−17).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([NH:28][C:29]3[NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[N:30]=3)[CH2:24][CH2:23]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].Cl.[CH2:46]([N:53]1[CH:57]=[CH:56][N:55]=[C:54]1[CH2:58]Cl)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[CH3:44][O:43][C:39]1[CH:38]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([NH:28][C:29]3[N:30]([CH2:58][C:54]4[N:53]([CH2:46][C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=5)[CH:57]=[CH:56][N:55]=4)[C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)[CH2:24][CH2:23]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccc(F)cc3)C2)cc(OC)c1OC
Reactant: ClCc1nccn1Cc1ccccc1
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5n4Cc4nccn4Cc4ccccc4)CC3)(c3ccc(F)cc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 37.2 using 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(4-fluorophenyl) pyrrolidine and 1-benzyl-1H-imidazol-2-ylmethylchloride hydrochloride to give the title compound: mp; 95-100° C. Rf=0.04 (silica gel, 1/1 ethyl acetate/methanol).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:27]([O:29][CH2:30][CH3:31])=[CH2:28])CCC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:30]([O:29][C:27]([C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1)=[CH2:28])[CH3:31]
Reactant: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=C(OCC)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61.6 %

Procedure:
To a degassed solution of 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quino-line (2.50 g, 5.86 mmol) in DMF (20 mL), was added Pd(Ph3P)4 (0.542 g, 0.469 mmol) and the solution was stirred for 20 min at room temperature. Then tributyl(1-ethoxyvinyl)stannane (2.117 g, 5.86 mmol) was added. The reaction was heated to 100° C. until LC-MS showed the reaction was complete. The reaction mixture was filtered through celite and the filtrate was washed with water, dried over Na2SO4, and concentrated. The resulting crude product was purified by silica gel column chromatography with gradient Hex:EA to give 6-((6-(1-ethoxyvinyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (1.2 g, 62%). 1H-NMR (400 MHz, CDCl3) δ ppm 9.19 (s, 1H), 8.94 (m, 1H), 8.20 (m, 1H), 7.99 (s, 1H), 7.89 (d, 1H), 7.548 (m, 1H), 6.12 (s, 2H), 5.61 (d, 1H), 4.61 (d, 1H), 4.05 (q, 2H), 1.51 (t, 3H). LCMS (method B): [MH]+=360, tR=2.40 min.
Reaction SMILES: [Br:1][CH2:2][C:3]([NH:5][C:6]1[C:7]([S:15][CH3:16])=[N:8][C:9]([CH3:14])=[CH:10][C:11]=1[S:12][CH3:13])=[O:4].ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)(Cl)Cl.O>[Br:1][CH2:2][C:3]([NH:5][C:6]1[C:7]([S:15]([CH3:16])=[O:25])=[N:8][C:9]([CH3:14])=[CH:10][C:11]=1[S:12][CH3:13])=[O:4]
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CBr
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CSc1cc(C)nc(S(C)=O)c1NC(=O)CBr
Temperature: 25 °C
Reaction time: 17 h
Yield: 20.4 %

Procedure:
To a solution of 2-bromo-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide (100 mg,0.311 mmol) in chloroform (2 ml) was added a solution of m-chloroperbenzoic acid (50 mg, 0.327 mmol) in chloroform (0.5 ml), and stirred at room temperature for 17 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated sodium chloride solution successively, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica gel preparative thin layer chromatography (developing solvent; chloroform:acetone=1:1) to provide 21.4 mg (yield 20%) of 2-bromo-N-[2(methanesulfinyl)-6-methyl-4-(methylthio)-3-pyridyl]acetamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH:13]=[CH:12][CH2:11][C@H:10]2[N+:15]([O-:17])=[O:16])=[CH:5][C:4]=1[O:18][CH3:19].[OH-].[K+].S(=O)(=O)(O)O>C(O)C.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH:13]=[CH:12][CH2:11][C@@H:10]2[N+:15]([O-:17])=[O:16])=[CH:5][C:4]=1[O:18][CH3:19]
Reactant: COc1ccc([C@@H]2CC=CC[C@H]2[N+](=O)[O-])cc1OC
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc([C@@H]2CC=CC[C@@H]2[N+](=O)[O-])cc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
10.0 g of (±)-trans-1,2-dimethoxy-4-(2-nitrocyclohex-4-enyl)benzene (compound I1) and 20.0 g of potassium hydroxide are dissolved in 150 ml of ethanol and 35 ml of dimethylformamide. A solution of 17.5 ml of conc. sulfuric acid in 60 ml of ethanol is then added dropwise such that the internal temperature does not exceed 4° C. After stirring for 1 h, the mixture is added to 1 l of ice water, the precipitate is filtered off with suction, washed with water and dried, and the crude product is recrystallized in ethanol. 8.6 g of the title compound of m.p. 82.5-84° C. are obtained.
Reaction SMILES: [N:1]1([CH2:6][C:7]23[CH2:15][CH:11]4[CH2:12][CH:13]([CH2:14]2)[C:9](C(O)=O)([CH2:10]4)[CH2:8]3)[CH:5]=[N:4][CH:3]=[N:2]1.OS(O)(=O)=O.[N-:24]=[N+]=[N-].[Na+]>C(Cl)(Cl)Cl.O>[N:1]1([CH2:6][C:7]23[CH2:15][CH:11]4[CH2:12][CH:13]([CH2:14]2)[C:9]([NH2:24])([CH2:10]4)[CH2:8]3)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(O)C12CC3CC1CC(Cn1cncn1)(C3)C2
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: NC12CC3CC1CC(Cn1cncn1)(C3)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a stirred suspension of 1-(1H-1,2,4-triazol-1-ylmethyl)tricyclo[3.3.1.03,7]nonane-3-carboxylic acid (0.13 g, 0.52 mmol) obtained in step III, in CHCl3 (2.6 mL) was added conc. H2SO4 (0.25 mL, 5.2 mmol). To this homogenous solution NaN3 (0.1 g, 1.56 mmol) was added in portions over a period of 30 minutes, while keeping the temperature of the reaction below 40° C. After stirring the reaction mixture for 2 h at r.t., the reaction mixture was cooled to ice bath temperature, diluted with water and extracted with EtOAc. The aqueous layer was basified by adding 50% aq. NaOH solution and extraction with CHCl3. The combined organic layer was washed with brine, dried over Na2SO4 and the solvent was removed under reduced pressure to obtain 1-(1H-1,2,4-triazol-1-ylmethyl)tricyclo[3.3.1.03,7]nonan-3-amine (0.08 g) as a viscous liquid in 70% yield. m/z (M+1) 219; 1H NMR (CDCl3) 300 MHz δ 7.98 (s, 1H), 7.93 (s, 1H), 4.07 (s, 2H), 2.38-2.30 (m, 1H), 2.06-1.98 (m, 1H), 1.96-1.80 (m, 2H), 1.72-1.57 (m, 4H), 1.55-1.36 (m, 4H).