Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([NH:17][C:18]2[N:19]=[C:20]([C:24]([NH:26][C:27]3[CH:28]=[C:29]([C:33]([NH:35][C:36]4[CH:37]=[C:38]([C:42]([OH:44])=O)[N:39]([CH3:41])[CH:40]=4)=[O:34])[N:30]([CH3:32])[CH:31]=3)=[O:25])[N:21]([CH3:23])[CH:22]=2)=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[N:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[S:52][S:53][CH2:54][CH2:55][NH2:56].CCN(C(C)C)C(C)C.C(Cl)CCl>CC(N(C)C)=O>[CH3:14][N:12]1[C:11]([C:15](=[O:16])[NH:17][C:18]2[N:19]=[C:20]([C:24](=[O:25])[NH:26][C:27]3[CH:28]=[C:29]([C:33](=[O:34])[NH:35][C:36]4[CH:37]=[C:38]([C:42](=[O:44])[NH:56][CH2:55][CH2:54][S:53][S:52][C:47]5[CH:48]=[CH:49][CH:50]=[CH:51][N:46]=5)[N:39]([CH3:41])[CH:40]=4)[N:30]([CH3:32])[CH:31]=3)[N:21]([CH3:23])[CH:22]=2)=[CH:10][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:13]1
Reactant: Cn1cc(NC(=O)c2cc(NC(=O)c3nc(NC(=O)c4cc(NC(=O)OC(C)(C)C)cn4C)cn3C)cn2C)cc1C(=O)O
Reactant: NCCSSc1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CC(=O)N(C)C
Product: Cn1cc(NC(=O)c2cc(NC(=O)c3nc(NC(=O)c4cc(NC(=O)OC(C)(C)C)cn4C)cn3C)cn2C)cc1C(=O)NCCSSc1ccccn1
Yield: 68.2 %

Procedure:
4-(4-(4-(4-(tert-butoxycarbonylamino)-1-methyl-1H-pyrrole-2-carboxamido)-1-methyl-1H-imidazole-2-carboxamido)-1-methyl-1H-pyrrole-2-carboxamido)-1-methyl-1H-pyrrole-2-carboxylic acid (102 mg, 0.17 mmol), 2-(pyridin-2-yldisulfanyl)ethanamine hydrogen chloride salt (40 mg, 0.18 mmol), DIPEA (30 ul, 0.17 mmol) and EDC (200 mg, 1.04 mmol) in 2 ml of DMA were stirred under Ar for 24 h, evaporated and purified on SiO2 chromatography eluted with THF/DCM (1:5 to 1:4) to afford 90 mg (68%) of the title compound. 1H NMR (DMSO) 10.93 (s, 1H), 10.19 (s, 1H), 10.06 (s, 1H), 9.03 (s, 1H), 8.81 (m 1H), 8.29 (m, 1H), 8.03 (m, 1H), 7.68 (s, 1H), 7.47 (s, 1H), 7.28 (s, 1H), 7.24 (s, 1H), 7.18 (m, 1H), 6.87 (s, 1H), 3.96 (s, 1H), 3.86 (s, 3H), 3.75 (s, 3H), 3.73 (s, 3H), 3.58 (m, 2H), 2.48 (m, 2H), 1.45 (s, 9H); MS m/z+798.0 (M+Na), 776.0 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[NH4+].[Cl-:15]>>[Cl:5][C:6]1[CH:13]=[CH:12][C:9](/[CH:10]=[CH:1]/[C:2](=[O:3])/[CH:4]=[CH:10]/[C:9]2[CH:12]=[CH:13][C:6]([Cl:15])=[CH:7][CH:8]=2)=[CH:8][CH:7]=1
Reactant: CC(C)=O
Reactant: [Cl-]
Reactant: O=Cc1ccc(Cl)cc1
Agent: [NH4+]
Product: O=C(/C=C/c1ccc(Cl)cc1)/C=C/c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.07 h
Yield: 34 %

Procedure:
A mixture of LiClO4 (1.2 g, 11 mmol), acetone (418 μL, 5.7 mmol) and 4-chloro-benzaldehyde (1.6 g, 11 mmol) was treated with TEA (159 μL, 1.1 mmol) and stirred for 4 min at ambient temperature. A saturated aq. NH4Cl solution was added to the reaction mixture and extracted with CH2Cl2. The combined organic layers were dried with MgSO4, filtered and the solvent was removed in vacuo. The residue was recrystallized from CH2Cl2 to obtain NW308 as yellow crystals (586 mg, 34%). mp: 182-184° C. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.60 (d, 3J=15.9 Hz, 2H, Hvin), 7.46 (d, 3J=8.5 Hz, 4H, HAr), 7.31 (d, 3J=8.5 Hz, 4H, HAr), 6.95 (d, 3J=15.9 Hz, 2H, Hvin). 13C NMR (75 MHz, CDCl3) δ (ppm): 188.3 (C), 142.0 (CH), 136.5 (C), 133.2 (C), 129.51 (CH), 129.2 (CH). MS (FAB) m/z: 303.1 (M+). Anal. calcd for C17H12Cl2O: C, 67.35; H, 3.99; Cl, 23.39. Found: C, 67.33; H, 4.01; Cl, 23.17%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:12][C@@H:13]([C@H:15]2[CH2:19][N:18]([C@@H:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH3:21])[C:17](=[O:30])[CH2:16]2)[CH3:14])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[Cl:11])[CH:7]=1.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][N:41]([C:44]2[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>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.O>[Cl:11][C:10]1[CH:9]=[N:8][N:6]2[CH:7]=[C:2]([C:47]3[CH:46]=[CH:45][C:44]([N:41]4[CH2:40][CH2:39][N:38]([C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])[CH2:43][CH2:42]4)=[CH:49][CH:48]=3)[CH:3]=[C:4]([O:12][C@@H:13]([C@@H:15]3[CH2:16][C:17](=[O:30])[N:18]([C@@H:20]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH3:21])[CH2:19]3)[CH3:14])[C:5]=12
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Br)cn4ncc(Cl)c34)CC2=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cn4ncc(Cl)c34)CC2=O)cc1
Temperature: 100 °C

Procedure:
To an appropriate sized microwave vial, (R)-4-((R)-1-((6-bromo-3-chloropyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 6.36 (118 mg, 0.239 mmol), (4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)boronic acid (73.3 mg, 0.239 mmol), cesium carbonate (234 mg, 0.718 mmol), dioxane (2.0 mL) and water (0.5 mL) were added. The mixture was degassed with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) catalyst (27.7 mg, 0.0239 mmol) was added and the solution was heated at 100° C. for 18 h. After cooling to room temperature, the reaction was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford tert-butyl 4-(4-(3-chloro-4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)phenyl)piperazine-1-carboxylate 6.38.
Reaction SMILES: [C:1]1([N:7]=[C:8](Cl)[C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:14]=[N+:15]=[N-:16].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]1([N:7]2[C:8]([C:9]([F:12])([F:11])[F:10])=[N:16][N:15]=[N:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: FC(F)(F)C(Cl)=Nc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: FC(F)(F)c1nnnn1-c1ccccc1
Temperature: 25 °C
Yield: 93.2 %

Procedure:
Five grams (24.1 mmol) of N-phenyl-2,2,2-trifluoroacetimidoyl chloride obtained in Example 1, 2.83 g (43.4 mmol) of sodium azide, 1.66 g (12.1 mmol) of triethylamine hydrochloride, and 40 ml of toluene were introduced into a 100 ml flask and reacted at 80° C. for 16.5 hours. After the reaction, the reaction solution was cooled to room temperature and washed with water (30 ml×3). The organic phase was dried over anhydrous magnesium sulfate for 1 hour, filtered, and then subjected to solvent removal by evaporation. The crude product thus obtained was purified by column chromatography (silica gel, ethyl acetate:hexane=3:7), resulting in 4.81 g of 1-phenyl-5-(trifluoromethyl)-1H-tetrazole as a pale yellow oil (yield: 93.2%). IR (neat, cm−1): 3071, 1531, 1499, 1312, 1207, 1167, 1013, 766, 691 1H-NMR (CDCl3): δ 7.60-7.54 (m, 3H), 7.38 (d, J=8.7 Hz, 2H), 7.06 (d, J=8.7 Hz, 2H), 3.89 (s, 3H) 13C-NMR (CDCl3): δ 145.90 (q, J=42.0 Hz), 132.41, 131.59, 131.58, 129.79, 129.76, 125.05, 117.73 (q, J=270.0 Hz) Elemental analysis: Value calculated for C8H5F3N4: C, 44.87%; H, 2.35%; N, 26.16% Value found: C, 44.27%; H, 2.24%; N, 25.95% Decomposition temperature (DSC): 290° C. (1.17 kJ/g), 367° C. (1.55 kJ/g)
Reaction SMILES: C[Al](C)C.COC(=O)[C@@H](OC)C1C=CC=CC=1.[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21].[CH3:25][O:26][CH:27]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:28]1[NH:29][CH:30]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:32]=1>>[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21].[CH3:25][O:26][CH:27]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:28]1[NH:32][C@H:31]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C@H:30]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:29]=1
Reactant: COC(C1=NC(c2ccccc2)C(c2ccccc2)N1)c1ccccc1
Agent: COC(=O)[C@@H](OC)c1ccccc1
Agent: C[Al](C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(C1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1)c1ccccc1

Procedure:
Employing the general trimethylaluminum coupling procedure and using methoxy-(S)-phenyl-acetic acid methyl ester prepared in accordance with Step 1 as described above and meso-1,2-diphenylethylene-diamine there was made, 2-(Methoxy-phenyl-methyl)-4,5-diphenyl-4,5-dihydro-1H-imidazole trifluoroacetate. 1H NMR (DMSO) δ 11.11 (bs, 1H), 7.7-7.5 (m, 5H), 7.1-7.0 (m, 6H), 6.90-6.85 (m, 2H), 6.8-6.7 (m, 2H), 5.81 (s, 2H), 5.65 (s, 1H), 3.49 (s, 3H); LC/MS: 3.69 min/m/z 343 (M++1)
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:1][C:12]1[CH:11]=[C:10]2[C:6]([C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:9]2)=[CH:5][C:4]=1[Cl:3]
Reactant: CCOC(=O)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c2cc(Br)c(Cl)cc2c1-c1ccccc1
Reaction time: 8 h

Procedure:
Add 11 ml (33 g.) of bromine to a mixture of ethyl 5-chloro-3-phenylindole-2-carboxylate (30 g.) in 100 ml of acetic acid at 10°-20°. Stir overnight and then add a solution of sodium bisulfite. Filter and wash the precipitate with water. Stir the solid with methanol and filter to yield the title compound. Recrystallization from methanol yields the analytical sample; m.p. 205°-206° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:12].[Na+].[CH2:14]=O>O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH:6]=1)[CH2:14][OH:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: C=O
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1ccc(O)c(CO)c1
Reaction time: 120 h
Yield: 50 %

Procedure:
In a 1-liter Erlenmeyer flask 150 g (1.00 mole) of p-t-butylphenol, 56 g (1.4 formulas) of sodium hydroxide dissolved in 400 ml of water, and 120 ml (1.6 moles, 40 g CH2O/100 ml solution) of formaldehyde solution were combined. The mixture was kept at 50° in a water bath for 5 days with occasional swirling. (After 10 minutes the mixture had become a nearly clear solution, but cloudiness began to increase after an additional 5 minutes.) The precipitated solid product was suction filtered, washed with a little water, and sucked as dry as possible. This still moist salt was neutralized by treatment with about 600 ml of 10% acetic acid. The new solid which formed was filtered and washed with water to give 107.9 g, m.p. 65°-85°. Two recrystallizations from hexane with a small amount of ether added yielded 90.1 g (50%) of 5-t-butyl-2-hydroxybenzyl alcohol m.p. of 91°-92°. The NMR spectrum of this compound (3.1τ, multiplet, 3 protons, aromatic; 6.1, broad singlet, 2, OH; 5.42, singlet, 2, CH2 ; 8.80, singlet, 9, C(CH3)3) is interesting in that the two nonequivalent hydroxyls appear to give only one peak. This is probably caused by time averaging of the two hydroxy protons due to hydrogen bonding and the acidity of the phenolic proton.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[N:10]1([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3([CH2:31][N:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1.N1C=CC=CC=1>ClCCl>[CH3:1][S:2]([N:35]1[CH2:36][CH2:37][N:32]([CH2:31][C:25]2([C:22]3[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][CH2:15][N:10]4[CH2:11][CH2:12][CH2:13][CH2:14]4)=[CH:24][CH:23]=3)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[CH2:33][CH2:34]1)(=[O:5])=[O:3]
Reactant: c1cc(C2(CN3CCNCC3)CCCCC2)ccc1OCCCN1CCCC1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)N1CCN(CC2(c3ccc(OCCCN4CCCC4)cc3)CCCCC2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.2 %

Procedure:
Methanesulphonic acid anhydride (49 mg, 0.28 mmol) was added at 0° C. to a solution of 1-({1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexyl}methyl) piperazine (90 mg, 0.23 mmol) and pyridine (47 μl, 0.58 mmol) in dichloromethane (1 ml). The reaction was stirred at 0° C. for 10 minutes, then allowed to warm up to room temperature and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure and partitioned between dichloromethane (20 ml) and aqueous sodium carbonate (20 ml). The layers were separated. The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (96:4:0.4 by volume) to provide the title compound (61 mg, 56%). 1H NMR (400 MHz, CDCl3) δ 1.29-1.36 (m, 3H), 1.45-1.52 (m, 5H), 1.85-1.90 (m, 4H), 2.08-2.15 (m, 4H), 2.22 (t, 4H), 2.32 (s, 2H), 2.67-2.79 (m, 9H), 3.00-3.03 (m, 4H), 4.02 (t, 2H), 6.83 (d, 2H), 7.24 (d, 2H). HRMS ESI+ m/z 464.2931 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:14]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)=[N:15][CH:16]=[CH:17][CH:18]=1>>[Cl:12][C:13]1[C:14]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)=[O:24])=[CH:21][CH:20]=2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc2cccnc2c1
Reactant: O=C(O)c1ccc(-c2ncccc2Cl)cc1
Product: O=C(Nc1ccc2cccnc2c1)c1ccc(-c2ncccc2Cl)cc1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (25 mg, 0.14 mmol) and 4-(3-Chloro-2-pyridyl)-benzoic acid (D84) (50 mg, 0.17 mmol) as a brown solid. MS(ES): MH+ 362/360, M-H+ 360/358.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:26][CH3:27])=[CH:12][CH:11]=2)=[O:9])[CH:2]=1.O.NN>[Ni].CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([NH2:23])[CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:26][CH3:27])=[CH:12][CH:11]=2)=[O:9])[CH:2]=1
Reactant: COc1ccc(C(=O)Nc2cccnc2)c2c1oc1ccc([N+](=O)[O-])cc12
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)Nc2cccnc2)c2c1oc1ccc(N)cc12
Yield: 65.4 %

Procedure:
N1-(pyrid-3-yl)-4-methoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide (500 mg) (from step1) was reduced using raney nickel (150 mg) (30% w/w aqueous suspension) in methanol (10 ml) in the presence of hydrazine hydrate (0.32 ml) under gentle reflux for 4 h. The reaction mixture was flitered through celite and the filterate was concentrated in vaccuo. The residue was triturated with water, to obtain a solid which was filtered dried to give the product as white solid (300 mg).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([CH3:12])[CH:6]=1)=[O:4].[CH3:13][CH:14](C)[CH2:15]N(C=CC)CC(C)C.[OH:25][CH2:26][C:27]([CH3:31])([CH2:29][OH:30])[CH3:28].S(=O)(=O)(O)O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C(#N)C>[CH3:28][C:27]1([CH3:31])[CH2:29][O:30][CH:13]([CH:14]([CH3:15])[CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([CH3:12])[CH:6]=2)=[O:4])[O:25][CH2:26]1
Reactant: Cc1ccc(C(=O)CBr)cc1C
Reactant: CC(C)(CO)CO
Reactant: CC=CN(CC(C)C)CC(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Product: Cc1ccc(C(=O)CC(C)C2OCC(C)(C)CO2)cc1C
Temperature: 50 °C
Reaction time: 4 h
Yield: 83.2 %

Procedure:
2-Bromo-1-(3,4-dimethylphenyl)ethan-1-one (6.2 g) and N,N-bis(2-methylpropyl)-1-propenylamine (6.8 g) were added to 25 ml of acetonitrile under an atmosphere of nitrogen and the mixture was stirred at around 50° C. for 4 hours. After cooling the reaction mixture to 10° C., 25 ml of water, 4.3 g of neopentyl glycol, 6.2 g of concentrated sulfuric acid and 0.62 g of para-toluenesulfonic acid were added to the reaction mixture and the mixture was stirred at around 60° C. for 1 hour. After cooling the reaction mixture to the room temperature, crystals precipitated. These crystals were isolated by filtration to give 6.6 g (yield 84%) of the title compound as white crystals.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=3)=[CH:12][CH:11]=2)=[C:5]([O:25][CH3:26])[CH:4]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].FC1C=C(F)C(F)=CC=1C1C=CC(OCC2C=C(NS(C)(=O)=O)C=CC=2)=CC=1>N1C=CC=CC=1>[F:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][C:18]3[CH:19]=[C:20]([NH:24][S:35]([CH3:34])(=[O:37])=[O:36])[CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:15]=2)=[C:5]([O:25][CH3:26])[CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc(N)c2)cc1
Agent: CS(=O)(=O)Nc1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc(NS(C)(=O)=O)c2)cc1
Yield: 53.2 %

Procedure:
A solution of 3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-phenylamine hydrochloride (101 mg, 0.269 mmol), triethylamine (38 uL, 0.269 mmol) and methanesulfonyl chloride (27 uL, 0.349 mmol) in dry pyridine (4 mL) was reacted similar to N-[3-(2′,4′,5′-trifluoro-biphenyl-4-yloxymethyl)-phenyl]-methanesulfonamide above. The crude product was purified by flash chromatography with a 0-15% gradient of ethyl acetate in hexanes to yield 60 mg of N-[3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-phenyl]-methanesulfonamide as a white solid. LC-MS (ES) calculated for C21H19F2NO4S, 419.45; found m/z 418 [M−H]−.
Reaction SMILES: [BH4-].[Na+].[S:3]1[C:7]([C:8]2[N:9]3[CH2:17][CH2:16][N:15]=[C:10]3[S:11][C:12]=2[CH:13]=[O:14])=[CH:6][C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]1=2.O>CO>[S:3]1[C:7]([C:8]2[N:9]3[CH2:17][CH2:16][N:15]=[C:10]3[S:11][C:12]=2[CH2:13][OH:14])=[CH:6][C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]1=2
Reactant: O=CC1=C(c2cc3ccccc3s2)N2CCN=C2S1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCC1=C(c2cc3ccccc3s2)N2CCN=C2S1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.4 %

Procedure:
Sodium borohydride (0.144 g) was added in portions over 10 minutes to a stirred suspension of 3-(benzo[b]thiophen-2-yl)-5,6-dihydroimidazo[2,1-b]-thiazole-2-carboxaldehyde (0.73 g) in methanol (20 ml), then the mixture was stirred at ambient temperature for 2 hours and allowed to stand at ambient temperature for 18 hours. Water (35 ml) was added and the mixture was stirred at ambient temperature for 10 minutes. The resulting solid was collected by filtration and dissolved in a 9:1 mixture of dichloromethane and ethanol (50 ml). The solution was dried (Na2SO4) and the solvents were removed in vacuo to give [3-(benzo[b]thiophen-2-yl)-5,6-dihydroimidazo[2,1-b]thiazol-2-yl]methanol (0.275 g) as a brown solid, m.p. 138-140° C.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[CH3:7][NH:8][CH2:9][CH2:10][CH2:11][OH:12].Br[CH2:14][CH2:15][CH2:16]Br>C(O)C>[CH3:7][N:8]([CH2:9][CH2:10][CH2:1][OH:4])[CH2:14][CH2:15][CH2:16][N:8]([CH3:7])[CH2:9][CH2:10][CH2:11][OH:12]
Reactant: CNCCCO
Reactant: BrCCCBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN(CCCO)CCCN(C)CCCO
Yield: 55.5 %

Procedure:
15 g of anhydrous potassium carbonate are added to a solution of 9 g of 3-methylaminopropanol and 10 g of 1,3-dibromopropane in 100 ml of ethanol, and the reaction mixture is stirred and refluxed for 24 hours. The mixture is allowed to cool, filtered, the filtrate is evaporated, and the residue is distilled. 6 g of N,N'-dimethyl-N,N'-bis(3-hydroxypropyl)-1,3-diaminopropane are obtained; b.p.: 150°-154° C/2 mmHg, nD20 = 1.4793.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1C(=NO)C(=C)[C:17]([O:23][C:24]([F:33])([F:32])[CH:25]([F:31])[O:26][C:27]([F:30])([F:29])[F:28])=[N:16]1.C([N:36]([CH2:39][CH3:40])CC)C.F[C:42](F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[C:39]([C:40]1[N:15]([C:3]2[CH:4]=[C:5]([S:9][CH2:10][C:11]([F:14])([F:12])[F:13])[C:6]([CH3:8])=[CH:7][C:2]=2[F:1])[N:16]=[C:17]([O:23][C:24]([F:32])([F:33])[CH:25]([F:31])[O:26][C:27]([F:28])([F:29])[F:30])[CH:42]=1)#[N:36]
Reactant: CCN(CC)CC
Reactant: C=C1C(OC(F)(F)C(F)OC(F)(F)F)=NN(c2cc(SCC(F)(F)F)c(C)cc2F)C1=NO
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)OC(F)(F)F)cc2C#N)cc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.6 %

Procedure:
Then, 0.28 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-(hydroxyimino)methylene-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole was dissolved in 10 mL of tetrahydrofuran, 0.12 g of triethylamine was added, and 0.13 g of trifluoroacetic anhydride was slowly dropwise added under cooling with ice. After stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure, and extraction with ethyl acetate was carried out. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 0.28 g of 5-cyano-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=2[F:22])[C@@H:11]([CH3:23])[N:10]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:9]1=[O:29])(C)(C)C.[ClH:31]>CCOC(C)=O>[ClH:31].[NH2:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=2[F:22])[C@@H:11]([CH3:23])[N:10]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:9]1=[O:29]
Reactant: C[C@@H]1[C@H](c2c(F)ccc(F)c2F)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H]1[C@H](c2c(F)ccc(F)c2F)C[C@H](N)C(=O)N1CC(F)(F)F
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl[(3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]carbamate (122 mg, 0.277 mmol) in EtOAc (10 mL) was saturated with HCl (g) and aged for 30 min. The resulting mixture was concentrated in vacuo to give the title compound. MS: m/z=341.1 (M+1); 1H NMR (500 MHz, CD3OD) δ 7.33 (qd, 1H, J=9.3, 4.9 Hz), 7.05 (tdd, 1H, J=9.8, 3.7, 2.2 Hz), 4.78 (dq, 1H, J=15.4, 9.3 Hz), 4.22 (dd, 1H, J=12.2, 6.6 Hz), 4.06 (ddd, 1H, J=13.3, 4.5, 2.7 Hz), 3.97 (m, 1H), 3.73 (dq, 1H, J=15.4, 8.8 Hz), 2.91 (qt, 1H, J=12.7, 3.1 Hz), 2.36 (ddd, 1H, J=12.7, 6.4, 2.0 Hz), 1.22 (d, 3H, J=6.6 Hz).
Reaction SMILES: CC(C)=[CH:3][SiH2:4][CH2:5][CH2:6][SiH2:7][CH:8]=[C:9]([CH3:11])[CH3:10].[CH3:13][C:14]([O:19][Si:20]([CH3:23])([CH3:22])[CH3:21])([CH2:17][CH3:18])[C:15]#[CH:16].[C:24]1(C)C=CC=CC=1>>[CH3:13][C:14]([O:19][Si:20]([CH3:22])([CH3:23])[CH3:21])([CH2:17][CH3:18])[C:15]#[C:16][Si:4]([CH3:3])([CH3:24])[CH2:5][CH2:6][SiH2:7][CH:8]=[C:9]([CH3:10])[CH3:11]
Reactant: CC(C)=C[SiH2]CC[SiH2]C=C(C)C
Reactant: Cc1ccccc1
Reactant: C#CC(C)(CC)O[Si](C)(C)C
Product: CCC(C)(C#C[Si](C)(C)CC[SiH2]C=C(C)C)O[Si](C)(C)C

Procedure:
As in reaction conditions of Example XIX Step 1, to 3.29 mL of toluene, the 0.02 g carbonylchlorohydridebis(tricyclohexylphosphine)ruthenium(H) was added, and the reaction was carried out between 1.64 g 1,2-bis(dimethylvinylsilyl)ethane and 0.47 g 3-methyl-3-(trimethylsiloxy)pent-1-yne. Raw 1-{[3-methyl-3-(trim ethyl siloxy)-1-pentynyl]dimethylsilyl}-2-(dimethylvinylsilyl)ethane was obtained.