Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19](Br)[CH:20]=[CH2:21]>C(#N)C.OS([O-])(=O)=O.[K+].CCOC(C)=O>[CH2:21]([O:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][N:3]=[C:2]2[Cl:1])=[CH:7][CH:8]=1)[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: Oc1ccc2ccnc(Cl)c2c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=CCOc1ccc2ccnc(Cl)c2c1
Reaction time: 0.03 h
Yield: 19 %

Procedure:
1-Chloroisoquinolin-7-ol (4.87 gm, 20.34 mmol) and cesium carbonate (6.63 g, 20.34 mmol) were combined in acetonitrile (100 mL) and stirred for 2 min. Allyl bromide (1.76 mL, 20.34 mmol) was added and the reaction mixture stirred for 30 min. The reaction mixture was diluted with aqueous KHSO4 (40 mL) and EtOAc (100 mL) and stirred. The organic extract was removed, dried over Na2SO4, concentrated and chromatographed on silica gel using 20-50% EtOAc/hexanes to give 0.85 g of an oil which solidified upon storing in the freezer. LRMS (M+H)+=220.1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C@H:11]([CH:13]2[CH2:15][CH2:14]2)[CH3:12])=[O:9])=[N:6][CH:7]=1.Cl.Cl.C[Si](C)(C)CCOC[N:24]1[C:28]2[N:29]=[CH:30][N:31]=[C:32]([C:33]3[CH:34]=[N:35][N:36]([C:38]4([CH2:42][C:43]#[N:44])[CH2:41][NH:40][CH2:39]4)[CH:37]=3)[C:27]=2[CH:26]=[CH:25]1>>[C:43]([CH2:42][C:38]1([N:36]2[CH:37]=[C:33]([C:32]3[C:27]4[CH:26]=[CH:25][NH:24][C:28]=4[N:29]=[CH:30][N:31]=3)[CH:34]=[N:35]2)[CH2:41][N:40]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([NH:10][C@H:11]([CH:13]3[CH2:15][CH2:14]3)[CH3:12])=[O:9])=[N:6][CH:7]=2)[CH2:39]1)#[N:44]
Reactant: C[C@H](NC(=O)c1ccc(Br)cn1)C1CC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Agent: Cl
Product: C[C@H](NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)cn1)C1CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 3, Step 2-3 starting from 5-bromo-N-[(1S)-1-cyclopropylethyl]pyridine-2-carboxamide (Example 2, Step 1) and {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride. LCMS (M+H)+: m/z=468.2. 1H NMR (400 MHz, DMSO-d6): δ 12.60 (s, 1H), 9.14 (s, 1H), 8.90 (s, 1H), 8.60 (s, 1H), 8.26 (d, J=8.0 Hz, 1H), 7.97 (d, J=3.0 Hz, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.84 (m, 1H), 7.28 (m, 1H), 7.12 (dd, J=8.0, 3.0 Hz, 1H), 4.68 (d, J=8.0 Hz, 2H), 4.43 (d, J=8.0 Hz, 2H), 3.80 (s, 2H), 3.39 (m, 1H), 1.12 (t, J=7.0 Hz, 3H), 1.05 (m, 1H), 0.45 (m, 1H), 0.38 (m, 1H), 0.22 (m, 1H).
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[C:22]([O:30][CH2:31][C@@H:32]1[C:36]([O:38][C:39](=[O:41])[CH3:40])([CH3:37])[C@:35]([F:43])([CH3:42])[CH:34](OC(=O)C)[O:33]1)(=[O:29])[C:23]1C=CC=CC=1.Cl[Sn](Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(#N)C>[C:22]([O:30][CH2:31][C@@H:32]1[C:36]([O:38][C:39](=[O:41])[CH3:40])([CH3:37])[C@:35]([F:43])([CH3:42])[CH:34]([N:1]2[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]2=[O:3])[O:33]1)(=[O:29])[CH3:23]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: CC(=O)OC1O[C@H](COC(=O)c2ccccc2)C(C)(OC(C)=O)[C@@]1(C)F
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Solvent: CC#N
Product: CC(=O)OC[C@H]1OC(n2cc(C)c(=O)[nH]c2=O)[C@](C)(F)C1(C)OC(C)=O
Yield: 30.3 %

Procedure:
To a stirred solution of thymine (about 0.31 g, 2.48 mmol) in acetonitrile (about 6 ml) was added N,O-Bis(trimethylsilyl)acetamide at room temperature (about 3.6 ml, 16.3 mmol) and refluxed for about 2 hours. To this added ((2R,4R)-3,5-diacetoxy-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.38 gm, 1.24 mmol) in acetonitrile (about 6 ml) drop wise at about 0° C., and added SnCl4 (about 0.2 ml, 1.86 mmol) then refluxed for about 15 hours. Completion of the reaction mixture monitored by thin-layer chromatography and neutralized the reaction mixture with saturated sodium bicarbonate solution. Aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 60% ethyl acetate/hexane as eluent furnished title compound (0.14 g) as a colorless solid. Yield: 30%; 1H-NMR: 1H NMR (300 MHz, CDCl3): δ 8.22 (s, 1H), 7.13-7.12 (m, 1H), 6.34 (d, 1H, J=23.4 Hz), 4.59-4.50 (m, 2H), 4.16-4.09 (m, 1H), 2.94 (d, 3H, J=22.2 Hz), 2.12 (s, 3H), 1.95 (s, 3H), 1.77 (d, 3H, J=2.4 Hz), 1.55 (d, 3H, J=30 Hz); ES Mass: [M+1] 373 (10%), [M+Na] 395 (100%).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.ClCCl.COCCN(S(F)(F)[F:31])CCOC.C(=O)(O)[O-].[Na+]>O>[F:31][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(F)CC1
Temperature: 25 °C

Procedure:
A 1-L, round bottom flask was charged with 12.64 g (51.4 mmol) of benzyl 4-oxo-1-piperidinecarboxylate and 300 mL of dichloromethane. To the stirring solution at −78° C. was added 19 mL (102.8 mmol) of [bis(2-methoxyethyl)amino]sulfur trifluoride via addition funnel over a period of about 1 h. The reaction mixture was allowed to warm slowly to ambient temperature overnight. The reaction mixture was added portionwise with caution to a large extractor containing water and saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane (3×300 mL). The combined organic layers were washed once with saturated aqueous sodium bicarbonate solution, twice with 10% aqueous hydrochloric acid solution and saturated aqueous brine, dried over sodium sulfate, and concentrated in vacuo. Purification by flash chromatography on a Biotage® system (gradient, hexane to 65% ethyl acetate/hexane) afforded the desired product. LC/MS 242.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:30]([C:33]1[CH:34]=[C:35](O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])[CH3:31]>>[C:30]([C:33]1[CH:38]=[C:37]([CH:36]=[CH:35][CH:34]=1)[O:29][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1)(=[O:32])[CH3:31]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(F)cc3)CC2)c1
Product: CC(=O)c1cccc(OC(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(F)cc2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3-acetylphenol: ESMS m/e: 516.9 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:15][CH:14]=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:14]=[CH:15][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:18]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)CCC(=O)c1ccc(Br)cc1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)CCC(=O)c1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 105 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
A stirred mixture of (4-cyano-phenyl)boronic acid (0.220 g, 0.00150 mol), 4-(4-bromo-phenyl)-4-oxo-butyric acid, methyl ester (0.2715 g, 0.00100 mol), triethylamine (0.418 mL, 0.0030 mol), tri(O-toluyl)phosphine (0.0191 g, 0.0000628 mol) and palladium(II)acetate (0.0067 g, 0.000030 mol) in dry dimethylformamide (4.0 mL) was heated at 105° C. under nitrogen for 2 hours and allowed to cool. For convenience, allowed to stand overnight. The mixture was diluted with diethyl ether, and the resulting suspension was filtered through Celite. The Celite and filtercake were washed with additional diethyl ether then dichloromethane. The filtrate and washings were combined and washed with 0.5 M aqueous hydrochloric acid, water, 3% aqueous ammonium hydroxide, water, and brine. The organics were dried (Na2SO4) and rotary evaporated. The residue was dissolved (chloroform) and chromatographed on silica gel (35 g, 230-400 mesh), eluting with hexanes-acetone (4:1, 30×30 mL) to give 0.172 g of 4-(4′-cyano-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester as a pale yellow solid; mp 149-151° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:4]=1[CH2:5][NH2:6].C(N(CC)CC)C.C([O:23][C:24]1[C:25](=[O:34])[C:26](=O)[C:27]=1[NH:28][C:29]([CH3:32])([CH3:31])[CH3:30])CCC>O1CCCC1>[C:29]([NH:28][C:27]1[C:24](=[O:23])[C:25](=[O:34])[C:26]=1[NH:6][CH2:5][C:4]1[C:3]([Cl:2])=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:11])([CH3:32])([CH3:30])[CH3:31]
Reactant: NCc1c(Cl)cccc1Cl
Reactant: CCCCOc1c(NC(C)(C)C)c(=O)c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)Nc1c(NCc2c(Cl)cccc2Cl)c(=O)c1=O
Reaction time: 16 h
Yield: 38.1 %

Procedure:
To 2,6-dichlorobenzylamine hydrochloride from Example 5, Step 2 (1.06 g, 5.0 mmol) in tetrahydrofuran (10 mL ) was added triethylamine (0.505 g, 5.0 mmol) followed by 3-butoxy-4-tert-butylamino-cyclobut-3-ene-1,2-dione (1.13 g, 5.0 mmol, Example 1) and stirring was continued for approximately 16 hours. The reaction mixture was freed of solvent and the residue was triturated with water, with diethyl ether and dried. The white solid thus isolated was crystallized twice from methanol to give 0.623 g (38%) of the title compound as a white solid: mp 265°-6° C. dec (softens 263° C.); 1H NMR (DMSO-d6) δ7.55 (d, 2H), 7.49 (br m, 1H), 7.42 (m, 2H), 5.05 (d, 2H), 1.34 (s, 9H) ppm. IR (KBr): 3185, 1785, 1660 cm-1 ; MS (m/z) 326/328/330 (M+). HPLC indicates a major component (99.9%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[N:9]=1)[CH3:2].[C:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C@H:30]([NH:34][C:35]([O:37][CH2:38][CH:39]2[C:51]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[C:45]3[C:40]2=[CH:41][CH:42]=[CH:43][CH:44]=3)=[O:36])[C:31](O)=[O:32])=[CH:25][CH:24]=1)([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(OCC)(=O)C.O.CN(C=O)C>[C:18]([O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][C@H:30]([NH:34][C:35](=[O:36])[O:37][CH2:38][CH:39]2[C:51]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[C:45]3[C:40]2=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:31](=[O:32])[N:6]([CH2:5][CH:4]([O:15][CH2:16][CH3:17])[O:3][CH2:1][CH3:2])[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[N:9]=2)=[CH:27][CH:28]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: CCOC(CNCc1cccc(F)n1)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(CN(Cc1cccc(F)n1)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Yield: 94.5 %

Procedure:
To a mixed solution of (2,2-diethoxyethyl)((6-fluoropyridin-2-yl)methyl)amine (514 mg, 2.12 mmol) described in Production Example 1-1-1 and DMF (10 mL) were added a commercially available product of (2S)-3-(4-(tert-butoxy)phenyl)-2-(((9H-fluoren-9-ylmethoxy)carbonyl)amino)propanoic acid (886 mg, 2.12 mmol), triethylamine (355 μL, 2.54 mmol) and HATU (968 mg, 2.54 mmol) at room temperature. The resultant mixture was stirred at room temperature for 45 minutes. Water was added to the reaction mixture, and the resultant mixture was then extracted with ethyl acetate. An organic layer was washed with water and saturated brine, was then dried over anhydrous magnesium sulfate, and was then filtrated. The solvent was evaporated under a reduced pressure, and the resultant residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:1 and then ethyl acetate) to give the title compound (1.37 g, yield: 94%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O.C(OC)(OC)OC.[CH:21]([NH2:24])([CH3:23])[CH3:22].[BH4-].[Na+]>C1COCC1>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][NH:24][CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)N
Reactant: O=Cc1cccc(-c2nccs2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(OC)OC
Product: CC(C)NCc1cccc(-c2nccs2)c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
To a solution of 3-(1,3-thiazol-2-yl)benzaldehyde (15 g, 81 mmol, 1.0 eq) in THF (100 mL) was added trimethyl orthoformate (9.0 mL, 8.6 g, 81 mmol, 1.0 eq) followed by isopropyl amine (11 mL, 7.3 g, 120 mmol, 1.5 eq) and the resulting reaction was stirred at 23° C. for 16 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in methanol (100 mL). Sodium borohydride (6.1 g, 160 mmol, 2.0 eq) was added portionwise over 30 minutes and after addition was complete the reaction was stirred for an additional 30 minutes at 23° C. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate (200 mL) and 1M aqueous potassium carbonate solution. The aqueous layer was separated and extracted with ethyl acetate (50 mL×2) and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to yield N-[3-(1,3-thiazol-2-yl)benzyl]propan-2-amine (15 g, 80%) as a white solid. 1H NMR (400 MHz, DMSO): δ 7.91-7.86 (m, 2 H); 7.77-7.72 (m, 2 H); 7.39 (d, J=5.4 Hz, 2 H); 3.72 (s, 2 H); 2.73-2.63 (m, 1 H); 0.98 (d, J=6.2 Hz, 6 H). LRMS m/z (M+H) 233.2 found, 233.1 required.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11][C:12]([OH:14])=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:20][CH2:21]O>>[CH2:20]([O:13][C:12](=[O:14])[CH2:11][C:8]1([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1)[CH3:21]
Reactant: O=C(O)CC1(c2ccc(Br)cc2)CC1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CC1(c2ccc(Br)cc2)CC1

Procedure:
[1-(4-Bromo-phenyl)-cyclopropyl]-acetic acid (16.73 mmol) was treated with concentrated sulfuric acid (2 mL) in EtOH at 80° C. overnight. The mixture was concentrated and submitted to standard aqueous workup. The crude material was purified by preparative HPLC to afford the title compound.
Reaction SMILES: Cl[Si](C)(C)C.[C:6]([O:10][C:11](=[O:23])[C@@H:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]I)([CH3:9])([CH3:8])[CH3:7].[CH2:24]([O:31][C:32]1[CH:37]=[C:36](I)[CH:35]=[CH:34][C:33]=1[N:39]1[S:43](=[O:45])(=[O:44])[N:42]([CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[C:41](=[O:52])[CH2:40]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[C:6]([O:10][C:11](=[O:23])[C@@H:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][C:36]1[CH:35]=[CH:34][C:33]([N:39]2[CH2:40][C:41](=[O:52])[N:42]([CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[S:43]2(=[O:45])=[O:44])=[C:32]([O:31][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:37]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: CC(C)(C)OC(=O)N[C@@H](CI)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of zinc powder (645 mg, 9.9 mmol) in DMF (1 mL) under argon is added chlorotrimethylsilane (83 mg, 0.76 mmol) and the mixture is stirred at RT for 30 min. To this is added a solution of (R)-2-tert-butoxycarbonylamino-3-iodopropionic acid tert-butyl ester (1.1 g, 2.96 mmol) in DMF (1.8 mL) dropwise and the mixture is stirred at RT for 30 min. An additional 2.5 mL of DMF is added and any insoluble material is filtered. The filtrate is added to a mixture of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (900 mg, 1.65 mmol), tri-o-tolylphosphine (100 mg, 0.33 mmol) and Pd2(dba)3 (74 mg, 0.08 mmol) and the mixture is stirred at RT for 90 min. Water is added and the mixture is extracted with EtOAc. The organic phase is washed with water (2×) and brine then is dried over sodium sulfate. The solvent is remover under reduced pressure and the residue is purified by flash chromatography using EtOAc/hexane (10%) as eluent to give the title compound as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=1.[Br:29][CH2:30][CH2:31]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O.[NH4+].[Cl-]>C1COCC1>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:14][CH2:15]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:31][CH2:30][Br:29])[CH:22]=1
Reactant: OCCBr
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(O)c2)c1N
Agent: CCOC(=O)N=NC(=O)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(OCCBr)c2)c1N
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.1 %

Procedure:
To a solution of 3-[5-amino-4-(3-hydroxy-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide (472 mg, 1.26 mmol) in THF (dry, 20 mL) at 0° C. was added of 2-bromoethanol (785 mg, 6.3 mmol), PPh3 (1.3g, 5.04 mmol) and diethyl azodicarboxylate (877 mg, 5.04 mmol) and the mixture was stirred at room temperature for 72 h. An aqueous solution of NH4Cl was added then the THF layer was isolated. The aqueous layer was extracted by EtOAc. The combined organic phase was washed by brine, purified by preparatory HPLC, to provide the product as a white solid (360 mg, 59%). HPLC (4 minute 10-90 gradient) tR 2.72 min; MS m/z 483.14/485.09 [M+H]+.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[C:17](F)[F:18])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C1C=CC=CC=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C1(C)C=CC=CC=1>[F:18]/[CH:17]=[CH:16]/[C:13]1[CH:14]=[CH:15][C:10]([C@H:7]2[CH2:8][CH2:9][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]2)=[CH:11][CH:12]=1
Reactant: CCC[C@H]1CC[C@H](c2ccc(C=C(F)F)cc2)CC1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: CCC[C@H]1CC[C@H](c2ccc(/C=C/F)cc2)CC1
Temperature: 0 °C

Procedure:
To trans-4-propyl-[4-(2,2-difluoro-1-ethenyl)phenyl]cyclohexane (23.4 g, 0.089 mol) were gradually added benzene (50 ml) and a 70 wt. % toluene solution of sodium bis(2-methoxyethoxy)aluminum hydride (50 ml) at a reaction temperature of -5° C. or lower with stirring, followed by gradually raising the reaction temperature up to 0° C. over 20 minutes, pouring the reaction solution in ice water (500 ml), extracting the resulting product with toluene (300 ml), twice washing with 6N-HCl (300 ml), further washing with water till the aqueous layer became neutral, drying the toluene solution over anhydrous magnesium sulfate, filtering off the drying agent, distilling off toluene, dissolving the residue in heptane, purifying according to silica gel chromatography, vacuum-distilling (130° C., 1.2 mmHg), five times recrystallizing from a mixed solvent of heptane and ethanol (1:1) and drying to obtain the objective substance (2.66 g, 0.011 mol). This compound exhibited a CN point of 24° C. and an NI point of 70° C.
Reaction SMILES: CI.[NH2:3][C:4]1[CH:5]=[C:6]([C:10]2[C:18]([CH:19]=[CH:20][C:21]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]3[CH2:29][CH3:30])=[O:22])=[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]3[N:11]=2)[CH:7]=[CH:8][CH:9]=1.[C:31](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:31][NH:3][C:4]1[CH:5]=[C:6]([C:10]2[C:18]([CH:19]=[CH:20][C:21]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]3[CH2:29][CH3:30])=[O:22])=[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]3[N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCC1CCCCN1C(=O)C=Cc1c(-c2cccc(N)c2)nn2ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CCC1CCCCN1C(=O)C=Cc1c(-c2cccc(NC)c2)nn2ccccc12
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 26.7 %

Procedure:
A solution of methyliodide (0.84 g) in N,N-dimethylformamide (2 ml) was added dropwise to a stirred mixture of 1-[3-{2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl}-acryloyl]-2-ethylpiperidine (trans isomer) (1.50 g) and powdered potassium carbonate (0.28 g) in N,N-dimethylformamide (10 ml) at room temperature. After being stirred at room temperature for 2 hours and 50 minutes, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride aqueous solution, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (36 g) with a mixture of methylene chloride and acetonitrile (5:1) as an eluent. The fractions containing major product were combined and evaporated in vacuo to give crystals of 1-[3-{2-(3-methylaminophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine (trans isomer) (0.21 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:24]>C1(C)C=CC=CC=1.[Ag]=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([O:22][CH3:24])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(O)c1ccc(OCc2ccccc2)cc1
Reactant: CI
Agent: O=[Ag]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(OC)c1ccc(OCc2ccccc2)cc1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
40 g of ethyl 3-(4-benzyloxyphenyl)-3-hydroxypropionate, 75 g of silver oxide and 83 ml of iodomethane were initially charged in 350 ml of toluene and stirred in a closed vessel at bath temperature 70° C. for 24 hours. Then a further 20 ml of iodomethane were added and the mixture was stirred at bath temperature 70° C. for a further 48 hours. The reaction mixture was filtered through a short silica gel layer and washed with toluene, and then the toluene was removed under reduced pressure. The residue was purified on silica gel with the eluent ethyl acetate:n-heptane=1:2. This gave 22.9 g of ethyl 3-(4-benzyloxyphenyl)-3-methoxypropionate.