Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:6]=1[CH2:7][NH2:8])[CH:2]=[CH2:3].[O:15]1[C@@H:17]([C@@H:18]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16]1.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:6]=1[CH2:7][NH:8][CH2:16][C@@H:17]([OH:15])[C@@H:18]([NH:26][C:27](=[O:28])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(OC)cc1CN
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: C=CCOc1ccc(OC)cc1CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 90.3 %

Procedure:
Step AS (5). A mixture of 2-allyloxy-5-methoxybenzylamine (375 mg, 1.94 mmol), (2S,3S)-1,2-epoxy-3-(BOC-amino)-4-phenylbutane (818 mg, 3.1 mmol), and lithium perchlorate (514 mg, 4.85 mmol) in acetonitrile (6 mL) was stirred at 60° C. for 2.5 h. The reaction was concentrated and the residue was purified by silica gel chromatography, eluting with a mixture of 5% 2N ammonia in methanol and 95% EtOAc to yield 0.8 g of tert-butyl (2S,3R)-4-(2-(allyloxy)-5-methoxybenzylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate. The BOC-protected amine was dissolved in 10 mL 10% TFA/DCM and stirred at rt for 3 h. The reaction was concentrated under vacuum and the residue purified by reverse phase prep-HPLC to yield the titled compound as the ditrifluoroacetic acid salt (440 mg, 39%). LC-MS (M+H)+=357; 1H NMR (400 MHz, CD3OD) δ 7.30 (m, 5H) 7.00 (m, 3H) 6.10 (m, 1H) 5.40 (m, 1H) 5.30 (m, 1H) 4.61 (m, 2H) 4.22 (m, 3H) 3.76 (s, 3H) 3.66 (m, 1H) 3.18 (m, 1H) 2.90 (m, 3H).
Reaction SMILES: CC([N:5]([C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[O:15][CH3:16])[C:6](=[O:8])[O-:7])(C)C.[F:17][C:18]1[CH:19]=[N:20][C:21]2[C:26]([C:27]=1[C:28](=[CH2:33])[C:29]([O:31][CH3:32])=[O:30])=[N:25][C:24]([O:34][CH3:35])=[CH:23][CH:22]=2>>[CH3:18][C:27]([O:7][C:6]([NH:5][C@H:9]1[CH2:14][CH2:13][N:12]([CH2:33][CH:28]([C:27]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:34][CH3:35])[N:25]=3)[N:20]=[CH:19][C:18]=2[F:17])[C:29]([O:31][CH3:32])=[O:30])[CH2:11][C@H:10]1[O:15][CH3:16])=[O:8])([CH3:28])[CH3:26]
Reactant: CO[C@@H]1CNCC[C@@H]1N(C(=O)[O-])C(C)(C)C
Reactant: C=C(C(=O)OC)c1c(F)cnc2ccc(OC)nc12
Product: COC(=O)C(CN1CC[C@H](NC(=O)OC(C)(C)C)[C@H](OC)C1)c1c(F)cnc2ccc(OC)nc12
Yield: 142.8 %

Procedure:
The title compound was prepared according to the general method of Example 2(d) from 1,1-dimethylethyl[(3R,4S)-3-(methyloxy)-4-piperidinyl]carbamate (1.29 g, 5.63 mmol) and methyl 2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-2-propenoate (1.48 g, 5.63 mmol) to give the desired product (1.98 g, 71%).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10].C(OC(=O)C)(=O)C.C([Si](C=C)(C)O[Si](C)(C)C)=C>C1(C)C=CC=CC=1>[CH2:1]([Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCO[SiH](OCC)OCC
Reactant: C=Cc1ccccc1
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CCO[Si](CCc1ccccc1)(OCC)OCC
Temperature: 50 °C
Yield: 13 %

Procedure:
130 mg Of styrene and 217 mg of triethoxysilane were placed in a glass reaction tube and 0.0015 ml of acetic anhydride was added. Next, 0.0045 ml of a toluene solution of a 0-valent platinum complex of divinyltetramethyldisiloxane (platinum content: 0.04 Wt. %) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 30 minutes in an oil bath at 50° C. When the tube contents were analyzed by GC-MS following cooling, the conversion rate of styrene was 16% and phenethyltriethoxysilane was produced at a yield of 13%. The yield of (α-methylbenzyl) triethoxysilane was 2%.
Reaction SMILES: [CH2:1]([CH:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:6]([O:8][CH3:9])=[O:7])[C:2]#[C:3][CH3:4].[Li+].CC([N-]C(C)C)C.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:36])(=O)=O)=CC=1>C1COCC1>[CH2:1]([C:5]([F:36])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:6]([O:8][CH3:9])=[O:7])[C:2]#[C:3][CH3:4]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC#CCC(CCCCCCCC)C(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC#CCC(F)(CCCCCCCC)C(=O)OC
Temperature: 25 °C

Procedure:
This ester was again deprotonated with LDA in THF, as described above, and at −78° C. a solution of N-fluoro benzenesulfonimide (1.1 equivalents) in THF was added dropwise. The mixture was allowed to warm to room temperature, quenched with saturated ammonium chloride solution, and worked up as above. Chromatography on silica gel with 5% ethyl acetate in hexane provided methyl 2-(2-butynyl)-2-fluorodecanoate as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([NH:16]C(=O)OC(C)(C)C)[CH2:12][CH2:11]1>ClCCl.C(N(C(C)C)CC)(C)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC1CCN(Cc2ccc(Br)cc2)CC1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
To a solution of 4-bromo benzylbromide (1.0 g, 4.1 mmol) in dichloromethane (20 ml) and diisopropyletylamine (1 ml) was added tert-butyl 4-piperidinylcarbamate (1.0 g, 5.0 mmol). The solution was then stirred at room temperature over night. The solvent was evaporated and 25 ml of 50% TFA in dichloromethane was added to the resulting white solid. The mixture was then stirred at room temperature for 2 h and then evaporated to dryness. The resulting solid was dissolved in water and extracted with toluene. After removal of the toluene the water phase was made basic with 1M NaOH giving a pH of 13. The water phase was then extracted with dichloromethane 3 times and the combined extracts were dried and then evaporated to give the pure product as a slightly yellow oil (0.96 g, 3.6 mmol)
Reaction SMILES: [C:1]([C:4]1[C:5](F)=[C:6]2[O:10][C:9]([CH:11]3[CH2:13][CH2:12]3)=[N:8][C:7]2=[C:14]([C:17]#[N:18])[C:15]=1[CH3:16])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:27][N:28]([CH3:34])[C@H:29]1[CH2:33][CH2:32][NH:31][CH2:30]1.C(OCC)(=O)C>CS(C)=O.O>[C:1]([C:4]1[C:5]([N:31]2[CH2:32][CH2:33][C@H:29]([N:28]([CH3:34])[CH3:27])[CH2:30]2)=[C:6]2[O:10][C:9]([CH:11]3[CH2:13][CH2:12]3)=[N:8][C:7]2=[C:14]([C:17]#[N:18])[C:15]=1[CH3:16])(=[O:3])[CH3:2]
Reactant: CN(C)[C@H]1CCNC1
Reactant: CC(=O)c1c(C)c(C#N)c2nc(C3CC3)oc2c1F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)c1c(C)c(C#N)c2nc(C3CC3)oc2c1N1CC[C@H](N(C)C)C1
Temperature: 90 °C
Reaction time: 6 h
Yield: 58.5 %

Procedure:
6-Acetyl-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-82) (130 mg, 0.50 mmol) was dissolved in dimethyl sulfoxide (2.6 ml), triethylamine (177 μl, 1.26 mmol) and (3S)-3-(dimethylamino)pyrrolidine (96 μl, 0.76 mmol) were added, followed by stirring at 90° C. for 6 hours under nitrogen atmosphere. After cooling to room temperature, ethyl acetate was added, followed by fractionation with water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was evaporated away and the resulting residue was subjected to preparative thin-layer silica gel column chromatography, eluted with a mixed solvent of chloroform/methanol (10:1, v/v) followed by recrystallization and purification with a mixed solvent of diethyl ether/ethyl acetate/n-hexane to obtain the entitled compound (103 mg, 57%) as a red white solid.
Reaction SMILES: ClCC([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][C:12]([NH:14][CH:15]2[CH2:18][N:17]([S:19]([O-:22])(=[O:21])=[O:20])[C:16]2=[O:23])=[O:13])[N:10]=1)=O.[Na+:24].CNC(=S)[S-].[Na+]>O>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][C:12]([NH:14][CH:15]2[CH2:18][N:17]([S:19]([O-:22])(=[O:21])=[O:20])[C:16]2=[O:23])=[O:13])[N:10]=1.[Na+:24]
Reactant: O=C(CCl)Nc1nc(CC(=O)NC2CN(S(=O)(=O)[O-])C2=O)cs1
Agent: CNC(=S)[S-]
Agent: [Na+]
Solvent: O
Product: Nc1nc(CC(=O)NC2CN(S(=O)(=O)[O-])C2=O)cs1
Yield: 36.5 %

Procedure:
In 6 ml of water is dissolved 0.486 g of sodium 3-[2-(2-chloroacetamido-4-thiazolyl)acetamido]-2-oxoazetidine-1-sulfonate, and to the solution is added 0.154 g of sodium N-methyldithiocarbamate under ice-cooling and stirring. The mixture is treated as described in Example 3 to obtain 0.144 g of sodium 3-[2-(2-amino-4-thiazolyl)acetamido]2-oxoazetidine-1-sulfonate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[CH:3]=1.[OH:24][C@H:25]1[CH2:65][N:28]2[C:29](=[O:64])[C@@H:30]([NH:56][C:57](=[O:63])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60])[C@H:31]([CH3:55])[CH2:32][CH:33]([CH3:54])[CH2:34][CH2:35][CH:36]=[CH:37][C@@H:38]3[CH2:43][C@@:39]3([C:44](=[O:53])[NH:45][S:46]([C:49]3([CH3:52])[CH2:51][CH2:50]3)(=[O:48])=[O:47])[NH:40][C:41](=[O:42])[C@@H:27]2[CH2:26]1.CC(C)([O-])C.[K+].Cl>CS(C)=O>[CH:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:7]=[C:2]([O:24][C@H:25]3[CH2:65][N:28]4[C:29](=[O:64])[C@@H:30]([NH:56][C:57](=[O:63])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60])[C@H:31]([CH3:55])[CH2:32][CH:33]([CH3:54])[CH2:34][CH2:35][CH:36]=[CH:37][C@@H:38]5[CH2:43][C@@:39]5([C:44](=[O:53])[NH:45][S:46]([C:49]5([CH3:52])[CH2:51][CH2:50]5)(=[O:47])=[O:48])[NH:40][C:41](=[O:42])[C@@H:27]4[CH2:26]3)[CH:3]=[C:4]([C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)[N:5]=2)=[CH:9][CH:10]=1)([CH3:17])[CH3:16]
Reactant: CC(C)Oc1ccc(-c2cc(Cl)cc(-c3cnccn3)n2)cc1
Reactant: CC1CCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)C1
Agent: CC(C)(C)[O-]
Agent: CC1CC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)C1
Agent: CC1CC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)[C@@H]2C[C@@H](Oc3cc(-c4ccc(OC(C)C)cc4)nc(-c4cnccn4)c3)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)C1
Solvent: CS(C)=O
Product: CC1CCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)[C@@H]2C[C@@H](Oc3cc(-c4ccc(OC(C)C)cc4)nc(-c4cnccn4)c3)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)C1
Reaction time: 0.03 h

Procedure:
To a dry 2 dram vial equipped with a stir bar and charged with 2-(4-chloro-6-(4-isopropoxyphenyl)pyridin-2-yl)pyrazine (37 mg, 0.11 mmol) was added tert-butyl ((2R,6S,7R,13aS,14aR,16aS,Z)-2-hydroxy-7,9-dimethyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate (46 mg, 0.076 mmol). To the vial was added DMSO (1.25 mL). The mixture was stirred for 2 minutes to afford a red, homogeneous solution. To the solution was added potassium tert-butoxide (43 mg, 0.38 mmol) to afford a very deep amber solution. The solution was stirred at room temperature for 2 h. To the solution was added aq. 1M HCl (3 mL) upon which a solid precipitated. The mixture was transfered to a 125 mL reparatory funnel and was diluted with water:brine (20 mL:20 mL). The mixture was extracted with EtOAc (2×30 mL). The combined organics were dried over MgSO4; filtered; then concentrated in vacuo to afford tert-butyl ((2R,6S,7R,13aS,14aR,16aS,Z)-2-((2-(4-isopropoxyphenyl)-6-(pyrazin-2-yl)pyridin-4-yl)oxy)-7,9-dimethyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate as a solid residue. MS: MS m/z 900.6 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][C:11]#[N:12].Br[CH2:14][CH2:15]Br.[OH-].[Na+].[Br-]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1([C:11]#[N:12])[CH2:15][CH2:14]1
Reactant: BrCCBr
Reactant: N#CCc1cc(F)c(Cl)cc1Cl
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC1(c2cc(F)c(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(2,4-dichloro-5-fluorophenyl)acetonitrile (1 g, 4.9 mmol, Eq: 1.00) was dissolved in toluene (4 mL). 1,2-Dibromoethane (1.38 g, 634 μL, 7.35 mmol, Eq: 1.50), aqueous NaOH-solution (4.31 mL, 12.5 M; 53.9 mmol, Eq: 11.0) and tertrabutylammonium bromide (348 mg, 1.08 mmol, Eq: 0.22) were added to the above suspension and vigorously stirred at RT for 4 h. The reaction mixture was diluted with water and extracted with AcOEt. The organic solution was washed with 1 N aqueous HCl, then with brine, dried over Na2SO4, filtered and evaporated to dryness. The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 50% EtOAc in heptane) to yield example 461a) (1.13 g; 100%) as an off-white solid. 1H-NMR (CDCl3, 250 MHz) δ [ppm]: 7.51 (1 proton, d, 6.7 Hz); 7.16 (1, proton, d; 8.9 Hz); 1.76-1.80 (2 protons, m); 1.31-1.36 (2 protons, m)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:14])([CH2:12][CH3:13])[CH2:10][CH3:11].[C:15]([O:19][C:20](=[O:28])[NH:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH:24]=O)([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20](=[O:28])[NH:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][NH:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH2:12][CH3:13])([OH:14])[CH2:10][CH3:11])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(CC=O)NC(=O)OC(C)(C)C
Reactant: CCC(O)(CC)c1ccc(F)cc1N
Product: CCC(O)(CC)c1ccc(F)cc1NCCC(C)(C)NC(=O)OC(C)(C)C

Procedure:
The product is obtained analogously to intermediate product 1b starting from 3-(2-amino-4-fluorophenyl)pentan-3-ol and tert-butyl(1,1-dimethyl-3-oxopropyl)carbamate. The crude product is purified by column chromatography (silica gel, dichloromethane/MeOH 100:0→98:2). Yield: 7.70 g (99%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22](Cl)[N:21]=[CH:20][N:19]=3)[C@H:14]([CH3:25])[CH2:13]2)=[N:7][CH:6]=1)[CH3:2].[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[F:34].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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>[CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:30]4[CH:31]=[CH:32][C:33]([F:34])=[C:28]([Cl:27])[CH:29]=4)[N:21]=[CH:20][N:19]=3)[C@H:14]([CH3:25])[CH2:13]2)=[N:7][CH:6]=1)[CH3:2]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CCOC(=O)c1cnc(N2CCN(c3cc(Cl)ncn3)[C@H](C)C2)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(N2CCN(c3cc(-c4ccc(F)c(Cl)c4)ncn3)[C@H](C)C2)c(Cl)c1
Temperature: 80 °C

Procedure:
Bubble nitrogen through a mixture of 5-chloro-6-[4-(6-chloro-pyrimidin-4-yl)-3-(R)-methyl-piperazin-1-yl]-nicotinic acid ethyl ester (226 mg, 0.57 mmol), 3-chloro-4-fluorophenylboronic acid (99 mg, 0.57 mmol), K3PO4 (2M aqueous, 570 μL) and Pd(PPh3)4 (33 mg, 0.03 mmol) in dioxane for 10 mm. Heat the mixture to 80°C. for 16 h under a nitrogen atmosphere. Cool the mixture and partition between EtOAc and water. Dry (Na2SO4) the organic layer and concentrate under reduced pressure to yield the crude product. Purify the residue with preparative plate chromatography (2×2 mm thick) using 40% EtOAc/hexanes as the eluent to afford the title compound as a foam. 1H NMR (400 MHz, CDCl3): δ1.38 (m, 6H, 2 ×CH3), 3.16 (m, 1H), 3.31 (dd, 1H, J=11 Hz), 3.51 (m, 1H), 4.12 (d, 1H, J=12.8 Hz), 4.21 (d, 1H, J=13 Hz), 4.39 (m, 3H), 4.77 (Br s, 1H), 6.82 (s, 1H), 7.25 (m, 1H), 7.89 (m, 1H), 8.07 (d, 1H, J=7 Hz), 8.18 (s, 1H), 8.71 (s, 1H), 8.79 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]1[N:7]([CH3:8])[CH:6]([CH3:9])[CH2:5][N:4]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=O)=[CH:12][CH:11]=2)[CH2:3]1.[NH2:21][C:22]1[N:26](C(OC(C)(C)C)=O)[N:25]=[C:24]([CH2:34][CH2:35][C:36]2[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[C:38]([O:44][CH3:45])[CH:37]=2)[CH:23]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:43][O:42][C:40]1[CH:41]=[C:36]([CH2:35][CH2:34][C:24]2[NH:25][N:26]=[C:22]([NH:21][C:14](=[O:16])[C:13]3[CH:12]=[CH:11][C:10]([N:4]4[CH2:5][CH:6]([CH3:9])[N:7]([CH3:8])[CH:2]([CH3:1])[CH2:3]4)=[CH:20][CH:19]=3)[CH:23]=2)[CH:37]=[C:38]([O:44][CH3:45])[CH:39]=1
Reactant: CCOC(=O)c1ccc(N2CC(C)N(C)C(C)C2)cc1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CC(C)N(C)C(C)C4)cc3)n[nH]2)cc(OC)c1
Yield: 7.4 %

Procedure:
N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(3,4,5-trimethylpiperazin-1-yl)benzamide was prepared following the procedure as for Example 94, but starting from ethyl 4-(3,4,5-trimethylpiperazin-1-yl)benzoate (310 mg, 0.86 mmol), tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (225 mg, 0.65 mmol) and 1M NaHMDS (2.59 ml, 2.59 mmol) in THF (5 ml). The crude product was purified by reverse phase prep. HPLC (basic) using a 38-58% gradient of acetonitrile in water containing 1% 0.880 ammonia. The clean fractions were taken and evaporated to afford the title compound as a white solid (23 mg, 5.6%); 1H NMR (399.99 MHz, CDCl3) δ1.09 (6H, d), 2.17-2.28 (2H, m), 2.22 (3H, s), 2.56 (2H, t), 2.81-2.90 (4H, m), 3.48 (2H, d), 3.68 (6H, s), 6.22 (1H, t), 6.28 (2H, s), 6.56 (1H, s), 6.78 (2H, d), 7.68 (2H, d0, 8.86 (1H, s), 9.65 (1H, s). MS: m/z 464 (MH+).
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].[Na].[F:8][C:9]([F:19])([F:18])[C:10]([F:17])([F:16])[C:11](OCC)=[O:12]>C(OCC)C>[F:16][C:10]([F:17])([C:9]([F:19])([F:18])[F:8])[C:11]([CH2:2][C:1]([O:4][CH2:5][CH3:6])=[O:3])=[O:12]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)C(F)(F)C(F)(F)F
Agent: [Na]
Solvent: CCOCC
Product: CCOC(=O)CC(=O)C(F)(F)C(F)(F)F
Yield: 18.4 %

Procedure:
Ethyl acetate (20.26 g, 0.23 mole) and sodium metal (2.3 g, 0.10 g-atom) was added to ethyl pentafluoropropionate (20.26 g, 0.23 mole) and the mixture was refluxed with stirring until sodium metal was dissolved. After sodium metal was dissolved, dry diethyl ether (100 ml) was added and the solution was further reacted under reflux overnight. After completion of the reaction, the solvent was evaporated under reduced pressure and the resulting residue was made acidic with 50 ml of 15% sulfuric acid, while it was cool. The solution was extracted with diethyl ether and the ether layer was dried with anhydrous sodium sulfate. Diethyl ether was then distilled off by distilling at atmospheric pressure using a fractionating column packed with Raschig ring and the resulting residue was further distilled under reduced pressure to give 9.90 g (42.3%) of the title compound as a colorless liquid, b.p. 77°-78° C./80 mmHg. The structure of this compound was confirmed by IR and NMR.
Reaction SMILES: [CH3:1][C:2]([CH3:38])([CH3:37])[C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[C:19]([CH3:34])[C:20]3[O:24][C:23]([C:25]([N:27]([CH2:29][C:30]([OH:32])=[O:31])[CH3:28])=[O:26])=[CH:22][C:21]=3[CH:33]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:35].[BH4-].[Na+]>C1COCC1>[CH2:13]([C:12]([C:17]1[CH:18]=[C:19]([CH3:34])[C:20]2[O:24][C:23]([C:25]([N:27]([CH2:29][C:30]([OH:32])=[O:31])[CH3:28])=[O:26])=[CH:22][C:21]=2[CH:33]=1)([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([OH:36])[C:2]([CH3:37])([CH3:38])[CH3:1])=[C:7]([CH3:35])[CH:8]=1)[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c2oc(C(=O)N(C)CC(=O)O)cc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)c2oc(C(=O)N(C)CC(=O)O)cc2c1
Yield: 96.4 %

Procedure:
[(5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-7-methyl-benzofuran-2-carbonyl)-methyl-amino]-acetic acid (310 mg, 0.594 mmol) in THF (2.0 mL) are reacted with NaBH4 (45 mg, 1.19 mmol) analogous to Example 8 to yield title compound (300 mg, 97%). MS (ES) m/e: 522.3 (M−1), 524.3 (M+1)
Reaction SMILES: [CH3:1][SH:2].[OH-].[Na+].Cl[C:6]1[CH:7]=[CH:8][C:9]([N+:16]([O-:18])=[O:17])=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1>C(O)C>[N+:16]([C:9]1[CH:8]=[CH:7][C:6]([S:2][CH3:1])=[CH:11][C:10]=1[C:12]([F:15])([F:14])[F:13])([O-:18])=[O:17]
Reactant: CS
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
The sodium salt of methanethiol is formed by stirring a solution of methanethiol (100 g, 2.0 mole plus a slight excess), sodium hydroxide (80 g, 2.0 mole) and ethanol (2 l.) under nitrogen at 0°-5° C. for one hour. To this solution is rapidly added 5-chloro-2-nitrobenzotrifluoride (451.2 g, 2.0 mole). The solution is allowed to warm to room temperature overnight and then refluxed four hours, cooled, filtered and the solvent evaporated off under reduced pressure. The resulting oil is poured into cold water (1 l.), extracted with methylene chloride, dried over magnesium sulfate and the solvent evaporated under reduced pressure to afford a yellow solid. Recrystallization from hexane affords a product having a melting point of 47°-50° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][N:14](C(OC(C)(C)C)=O)[C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:46]=[C:45]4[C:41]([C:42]([CH3:47])=[N:43][NH:44]4)=[CH:40][CH:39]=3)=[CH:34][CH:33]=2)[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][NH:14][C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:46]=[C:45]4[C:41]([C:42]([CH3:47])=[N:43][NH:44]4)=[CH:40][CH:39]=3)=[CH:34][CH:33]=2)[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(COc4ccc(-c5ccc6c(C)n[nH]c6c5)cc4)nc(N)n3)CC2)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(COc4ccc(-c5ccc6c(C)n[nH]c6c5)cc4)nc(N)n3)CC2)CN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((4-(3-methyl-1H-indazol-6-yl)phenoxy)methyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (150 mg, 0.19 mmol) in CH2Cl2 (5 mL) was added TFA (3 mL), and the resulting mixture was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo, and the resulting material partitioned between CH2Cl2 and saturated NaHCO3, and extracted. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by prep-TLC (CH2Cl2/MeOH) provided (S)-ethyl 8-(2-amino-6-((4-(3-methyl-1H-indazol-6-yl)phenoxy)methyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a brown solid.