Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:7])[C:3]([CH3:6])([CH3:5])[CH3:4].[Br:9][C:10]1[C:15]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:13]=[CH:12][N:11]=1.N1C=CN=C1>CN(C=O)C.[OH-].[Na+]>[Br:9][C:10]1[C:15]([O:16][CH2:17][CH2:18][O:19][Si:2]([C:3]([CH3:6])([CH3:5])[CH3:4])([CH3:7])[CH3:1])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCOc1cccnc1Br
Agent: [Na+]
Agent: [OH-]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1cccnc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of dimethyl-t-butylsilyl chloride (11.1 g, 74 mmol) in DMF (30 mL) was added to a suspension of 2-bromo-3-(2-hydroxyethoxy)pyridine (15.3 g, 70 mmol; obtained in Example 191, Step 1) and imidazole (10.0 g, 147 mmol) in DMF (30 mL). The reaction mixture was stirred at ambient temperature for 2 h, diluted with 0.5 M aqueous NaOH (0.7 L), and extracted twice with toluene. The combined organic phases were washed once with water, dried (MgSO4), and concentrated. The resulting oil was treated with a mixture of petroleum ether and ethyl acetate (95:5; 50 mL) and an analytical sample of white crystals was collected. The remaining crystals were mixed with the filtrate, the solvent was evaporated and the resulting crude product was used directly in the next step. Solid; yield 18.3 g (78%); mp 81° C. Anal. (C13H22BrNO2Si) C,H,N.
Reaction SMILES: O[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([Cl:14])([Cl:13])[Cl:12])[O:8][CH:7](C(Cl)(Cl)Cl)[C:6]=2[CH:19]=1.C(Cl)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:14][C:11]([CH:9]1[O:8][CH2:7][C:6]2[CH:19]=[CH:2][CH:3]=[CH:4][C:5]=2[O:10]1)([Cl:13])[Cl:12]
Reactant: Oc1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Solvent: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1
Product: ClC(Cl)(Cl)C1OCc2ccccc2O1
Temperature: 25 °C

Procedure:
A mixture of 6-hydroxy-2,4-bis(trichloromethyl)benzo[1,3]dioxin (1.0 g.), benzoyl chloride (0.35 ml.) and toluene (20 ml.) was warmed on the steam bath for 1 hour. The resulting solution was cooled to ambient temperature and evaporated to dryness under reduced pressure to give an oily residue. The residue was triturated with ethanol (5 ml.) to give a white solid, which was crystallised from ethanol to give 6-benzoyloxy-2,4-bis(trichloromethylbenzo[1,3]dioxin, m.p. 167°-169° C.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[CH:4][N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC>O1CCCC1>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1ccc(Cl)nc1
Temperature: -20 °C
Reaction time: 3 h

Procedure:
In tetrahydrofuran (8 ml), 6-chloro-N-methoxy-N-methylnicotinamide (500 mg) was dissolved, followed by the dropwise addition of diisobutylaluminum hydride (a 0.95M hexane solution, 2.88 ml) at −78° C. in an argon gas atmosphere. The resulting mixture was stirred for 3 hours and then, at room temperature, for 2 hours. After the reaction mixture was cooled to −20° C., saturated saline (2 ml) was added thereto, followed by stirring for 30 minutes. The insoluble matter was filtered off. The residue was washed with ethyl acetate. The filtrate and the washing were combined together. The mixture was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure, whereby the title compound (346 mg, 98%) was obtained as a crude product. The product was provided for the subsequent reaction without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](C)=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cu]C#N.[CH3:16][N:17]([CH3:20])C=O>>[CH3:2][C:3]1[C:20]2[N:17]=[CH:16][CH:9]=[CH:8][C:7]=2[C:6]([C:11]#[N:10])=[CH:5][CH:4]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(Br)c2ncccc12
Agent: N#C[Cu]
Product: Cc1ccc(C#N)c2cccnc12
Temperature: 200 °C

Procedure:
4.0 g 8-Bromo-5-methyl-quinoline and 1.69 g copper (I) cyanide were dissolved in 16 ml dimethylformamide and stirred at 200° C. for thirty minutes under microwave irradiation. The cooled reaction mixture was poured in 50 ml 2N HCL and extracted with 100 ml ethyl acetate. The organic layer was washed with 50 ml 2N HCl and 30 ml brine and then dried over MgSO4. The solvent was removed in vacuo. The resulting residue was purified on silica gel with the eluent n-heptane ethyl acetate=2:1 to obtain 3.0 g 8-Methyl-quinoline-5-carbonitrile.
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11].C(C1C=CC=CC=1N)#[N:21]>>[C:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])#[N:21]
Reactant: N#Cc1ccccc1N
Reactant: O=C(Nc1ccccc1C(F)(F)F)C1CCCCC1
Product: N#Cc1ccccc1NC(=O)C1CCCCC1
Yield: 75 %

Procedure:
This compound was prepared following the procedure described for compound 26A in example 26, except that 2-cyanoaniline was used in place of 2-trifluoromethylaniline. Yield 75%. M.p. 135-137° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH2:11][CH:12](OC)[C:13]([O:15]C)=O)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C(O)(=O)C.O.[NH2:25][NH2:26]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:15])[NH:25][N:26]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: COC(=O)C(CC(=O)c1cc(Cl)c(C)c(Cl)c1)OC
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(Cl)cc(-c2ccc(=O)[nH]n2)cc1Cl
Yield: 86.2 %

Procedure:
1.53 g (0.005 mole) of methyl 4-(3,5-dichloro-4-methylphenyl)-2-methoxy-4-oxobutyrate were added to 4 ml of acetic acid and the mixture was heated to form a solution, to which was then added 0.275 g (0.0055 mole) of hydrazine monohydrate. The mixture was heated under reflux for 3 hours and then cooled, after which it was diluted with 40 ml of water and stirred. The resulting crystals were collected by filtration, washed successively with water and with a small amount of ethyl acetate and then air-dried, to give 1.1 g (yield 86.2%) of the desired 6-(3,5-dichloro-4-methylphenyl)-3(2H)pyridazinone, having properties the same as those of the preceding Examples.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3](O)O.[CH3:8][N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[Na+].[Na+].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O>[F:1][C:2]([F:7])([F:6])[CH:3]=[CH:8][N+:9]([O-:11])=[O:10]
Reactant: C[N+](=O)[O-]
Reactant: OC(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])C=CC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
A mixture of 2,2,2-trifluoroethane-1,1-diol (75% aq solution, 20 g, 0.13 mol), CH3NO2 (24 g, 0.39 mol) and Na2CO3 (0.85 g, 8 mmol) was stirred overnight at RT. Water (50 mL) was added and the mixture was extracted with diethyl ether (3×30 mL) and dried over Na2SO4. After concentrating the organic extract at low temperature and under reduced pressure, P2O5 (20.0 g, 0.14 mol) was added to the residue oil, which was distilled at atmospheric pressure to give a green-yellow oil (4 g, 50% purity, 10% yield). Boiling point 85-90° C.; 1H NMR (400 MHz, CDCl3) δ ppm 7.09-7.17 (m, 1 H), 7.50 (dd, J=2.0 Hz, 12.0 Hz, 1 H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:12](=[O:32])[NH:13][C@H:14]([B:19]1[O:27][C@H:26]2[C@:21]([CH3:31])([C@H:22]3[CH2:28][C@@H:24]([CH2:25]2)[C:23]3([CH3:30])[CH3:29])[O:20]1)[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:9]([CH3:11])[CH3:10])(C)(C)C.CC(O[C:39]([NH:41][C@H:42]([C:54]([OH:56])=O)[CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([O:52][CH3:53])[CH:45]=1)=[O:40])(C)C.[O:57]([C:64]1[CH:65]=[C:66]([CH2:70]C(O)=O)[CH:67]=[CH:68][CH:69]=1)[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>>[CH3:53][O:52][C:46]1[CH:45]=[C:44]([CH2:43][C@H:42]([NH:41][C:39](=[O:40])[CH2:70][C:66]2[CH:67]=[CH:68][CH:69]=[C:64]([O:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[CH:65]=2)[C:54]([NH:7][C@@H:8]([CH:9]([CH3:11])[CH3:10])[C:12]([NH:13][C@H:14]([B:19]2[O:27][C@H:26]3[C@:21]([CH3:31])([C@H:22]4[CH2:28][C@@H:24]([CH2:25]3)[C:23]4([CH3:30])[CH3:29])[O:20]2)[CH2:15][CH:16]([CH3:17])[CH3:18])=[O:32])=[O:56])[CH:49]=[CH:48][C:47]=1[O:50][CH3:51]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Reactant: O=C(O)Cc1cccc(Oc2ccccc2)c1
Reactant: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1OC
Product: COc1ccc(C[C@H](NC(=O)Cc2cccc(Oc3ccccc3)c2)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)B2O[C@@H]3C[C@@H]4C[C@@H](C4(C)C)[C@]3(C)O2)C(C)C)cc1OC

Procedure:
The title compound is prepared from {(S)-2-Methyl-1-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-butylcarbamoyl]-propyl}-carbamic acid tert-butyl ester by reiteration of the 2-step (deprotection/coupling) procedure described in example 1 but using Boc-L-3,4-dimethoxyphenylalanine (Synthetech) and (3-Phenoxyphenyl)-acetic acid (Trans World Chemicals, Inc.; Rockville, Md., USA) as the partners in each coupling reaction (step B, example 1), respectively. The title compound is obtained as a foam; ES-MS: 782.3 [M+H]+; HPLC: single peak at tR=11.76 min (System 1); Rf=0.61 (CH2Cl2/MeOH, 90/10).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=3)[N:13]=[C:12]2[CH3:27])[CH:5]=1.[Br:29]N1C(=O)CCC1=O>ClCCl>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Br:29])=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=3)[N:13]=[C:12]2[CH3:27])[CH:5]=1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C)n3)cc2=O)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C)n3)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.9 %

Procedure:
To a solution of 4-methyl-3-[2-methyl-4-(6-methyl-pyridin-2-ylmethoxy)-6-oxo-6H-pyrimidin-1-yl]-benzoic acid methyl ester from Step A (122 mg, 0.32 mmol) in dichloromethane (2 mL) was added N-bromosuccinimide (57 mg, 0.32 mmol). The solution was stirred at ambient temperature for two hours. The solution was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated to provide the brominated product as colorless oil (148 mg, quantitative yield). MS (M, M+2): 458, 460
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([N+:16]([O-])=O)[CH:8]=2)[CH:2]=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:29]([C:31]3[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=3)=[O:30])[CH:26]=2)[CH:21]=[CH:20]1>>[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:29](=[O:30])[C:31]3[CH:38]=[CH:37][C:34]([C:35]4[NH:16][C:9]5[CH:8]=[C:7]([C:3]6[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=6)[CH:12]=[CH:11][C:10]=5[N:13]=4)=[CH:33][CH:32]=3)[CH:26]=2)[CH:21]=[CH:20]1
Reactant: O=Cc1ccc(C(=O)Nc2ccc3cc[nH]c3c2)cc1
Reactant: O=[N+]([O-])c1ccc(-c2cccnc2)cc1[N+](=O)[O-]
Product: O=C(Nc1ccc2cc[nH]c2c1)c1ccc(-c2nc3ccc(-c4cccnc4)cc3[nH]2)cc1

Procedure:
Compound 650 was prepared according to the procedure similar to that described in Scheme III from 1-(3-pyridinyl)-3,4-dinitrobenzene and 4-(6-indolylaminocarbonyl)benzaldehyde. [M+H]+ calcd for C27H19N5O: 430.16; found: 429.96.
Reaction SMILES: CCO[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:25][CH2:24][CH:23]([CH3:26])[NH:22][C:21]=2[CH:27]=1>>[Cl:16][C:17]1[C:27]2[C:11](=[O:13])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:22]3[CH:23]([CH3:26])[CH2:24][O:25][C:20]([C:21]=23)=[CH:19][CH:18]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC1COc2ccc(Cl)cc2N1
Product: CCOC(=O)c1cn2c3c(ccc(Cl)c3c1=O)OCC2C

Procedure:
Using the method of Example 1, diethyl ethoxymethylene malonate is reacted with 6-chloro-3,4-dihydro-3-methyl-2H-1,4-benzoxazine and the product reacted with polyphosphoric acid to provide ethyl 8-chloro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate, m.p. 205°-206° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]([B-](F)(F)F)=[CH2:10].[K+].C(N(CC)CC)C>C(O)CC>[Cl:1][C:2]1[N:7]=[C:6]([CH:9]=[CH2:10])[CH:5]=[CH:4][N:3]=1
Reactant: C=C[B-](F)(F)F
Reactant: Clc1ccnc(Cl)n1
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCCO
Product: C=Cc1ccnc(Cl)n1
Temperature: 100 °C

Procedure:
A mixture of 2,4-dichloropyrimidine (4.4 g, 29.5 mmol), potassium vinyltrifluoroborate (4.58 g, 32.5 mmol), PdCl2 (dppf)-CH2Cl2 (1.21 g, 1.48 mmol) and triethylamine (4.12 mL, 29.5 mmol) in nPrOH (148 mL) was purged with nitrogen for 15 min, heated to 100° C. for 5 h, and cooled to room temperature. The mixture was treated with water and extracted with EtOAc (×3). The combined organics were washed with brine, dried (sodium sulfate), concentrated, and purified by flash chromotography to afford 2-chloro-4-ethenylpyrimidine as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 8.56 (d, J=5.1, 1H), 7.21 (d, J=5.1, 1H), 6.70 (dd, J=10.6, 17.4, 1H), 6.57-6.51 (m, 1H), 5.79 (dd, J=0.8, 10.6, 1H).
Reaction SMILES: Cl.[S:2]([N:12]1[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH2:22])[N:20]=[C:15]2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C@@H:33]([CH3:36])[C@@H:32]([C:37](O)=[O:38])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C@@H:33]([CH3:36])[C@@H:32]([C:37](=[O:38])[NH:22][CH2:21][C:19]2[N:20]=[C:15]3[CH:14]=[CH:13][N:12]([S:2]([C:5]4[CH:6]=[CH:7][C:8]([CH3:9])=[CH:10][CH:11]=4)(=[O:3])=[O:4])[C:16]3=[N:17][CH:18]=2)[CH2:31]1)=[O:29])([CH3:25])([CH3:26])[CH3:24]
Reactant: C[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CN)cnc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=O)[C@H]4CN(C(=O)OC(C)(C)C)CC[C@H]4C)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100.4 %

Procedure:
To a slurry of (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (34.0 g, 100 mmol, Example #5, Step C), (3R,4R)-1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic acid (24.43 g, 100 mmol) and HATU (38.2 g, 100 mmol) in DCM (700 mL) was added DIEA (52.6 mL, 301 mmol). The reaction was stirred at ambient temperature for about 45 min. The reaction was washed with saturated aqueous NaHCO3 (300 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered then concd in vacuo. The resulting residue was purified by chromatography on silica gel (330 g) using 33-100% EtOAc in heptane to give (3R,4R)-tert-butyl-4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate (53 g, 100%) as a pale-yellow foam: LC/MS (Table 1, Method b) Rt=2.40 min; MS m/z: 528 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH:9](SC1C=CC(Cl)=CC=1)[C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=1[F:18])[C:5](OC)=[O:6].CC(C[AlH]CC(C)C)C.[Cl:37][C:38]1[CH:39]=[C:40]([CH:45]=[CH:46][CH:47]=1)C(OO)=O.[O-:48][S:49]([O-:51])=O.[Na+].[Na+]>C1COCC1.O>[Cl:37][C:38]1[CH:39]=[CH:40][C:45]([S:49]([CH:9]([C:10]2[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=2[F:18])[CH:4]([CH2:5][OH:6])[CH2:3][OH:2])(=[O:51])=[O:48])=[CH:46][CH:47]=1
Reactant: O=S([O-])[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)C(C(=O)OC)C(Sc1ccc(Cl)cc1)c1c(F)ccc(F)c1F
Agent: CC(C)C[AlH]CC(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1c(F)ccc(F)c1F)C(CO)CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[(4-Chloro-phenylsulfanyl)-(2,3,6-trifluoro-phenyl)-methyl]-malonic acid dimethyl ester (7.1 g, 17 mmol) was dissolved in 50 mL THF and DIBAL-H (1M in hexane, 68 mL) was added. The reaction was stirred at room temperature overnight. 100 mL of water was added to quench the reaction and 100 mL EtOAc was added to extract the product. The organic layer was washed with 1N HCl solution (2×50 mL), brine (50 mL), dried over Na2SO4 and concentrated. The residue was dissolved in 200 mL DCM and mCPBA (77%, 7.6 g, 34 mmol) was added. The reaction was stirred at room temperature for three hours. 8 g Na2SO3 in 50 mL of water was added to quench excess mCPBA. The organic layer was separated, washed with 1N NaOH solution, brine, dried over Na2SO4 and concentrated. The product was purified by column using EtOAc/hex as the eluent (gradient from 0/100 to 75/25 in 40 min, 2.7 g, 40%). 1H NMR (CDCl3 400 MHz) δ 7.59 (m, 2H), 7.36 (m, 2H), 7.06 (m, 1H), 6.81 (m, 0.5H), 6.57 (m, 0.5H), 5.26 (d, J=11.0 Hz, 1H), 4.65 (m, 1H), 4.20 (dt, J=11.7 and 2.2 Hz, 1H), 3.93 (m, 1H), 3.42 (m, 1H), 3.02 (m, 1H).
Reaction SMILES: [O:1]=[C:2]([CH3:17])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([C:14]([OH:16])=O)=[CH:12][N:13]=2)[CH:10]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:29][C:30]1[CH:31]=[C:32]([C:37]2[N:41]=[C:40]([CH:42]3[CH2:45][N:44]([C:46]([O:48][CH3:49])=[O:47])[CH2:43]3)[O:39][N:38]=2)[CH:33]=[CH:34][C:35]=1[CH3:36]>ClCCl.N1C=CC=CC=1>[CH3:36][C:35]1[CH:34]=[CH:33][C:32]([C:37]2[N:41]=[C:40]([CH:42]3[CH2:43][N:44]([C:46]([O:48][CH3:49])=[O:47])[CH2:45]3)[O:39][N:38]=2)=[CH:31][C:30]=1[NH:29][C:14]([C:11]1[N:9]2[CH:10]=[C:5]([CH2:4][CH2:3][C:2](=[O:1])[CH3:17])[CH:6]=[CH:7][C:8]2=[N:13][CH:12]=1)=[O:16]
Reactant: CC(=O)CCc1ccc2ncc(C(=O)O)n2c1
Reactant: COC(=O)N1CC(c2nc(-c3ccc(C)c(N)c3)no2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5ccc(CCC(C)=O)cn45)c3)no2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring suspension of 6-(3-oxobutyl)imidazo[1,2-a]pyridine-3-carboxylic acid (78) (50 mg, 0.215 mmol) in anhydrous dichloromethane (2 mL) at 0° C. under Argon was added dropwise oxalyl chloride (20 uL, 0.237 mmol). Then, a drop of anhydrous N,N-dimethylformamide was added and the reaction mixture was stirred at 0° C. for 1 hour. The solvent was concentrated and the crude solid was dried under vacuo. Next, methyl 3-(3-(3-amino-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (31) (27 mg, 0.0796 mmol) and anhydrous pyridine (1 mL) were added to the acid chloride. The reaction was stirred to room temperature under Argon for 20 minutes. The crude product was purified by reverse phase preparative HPLC to give methyl 3-(3-(4-methyl-3-(6-(3-oxobutyl)imidazo[1,2-a]pyridine-3-carboxamido)phenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F65). 1H NMR (400 MHz, d6-DMSO) δ 10.02 (s, 1H), 9.31 (s, 1H), 8.55 (s, 1H), 8.10 (d, J=1.6 Hz, 1H), 7.83 (dd, J=2.0, 8.0 Hz, 1H), 7.73 (d, J=9.2 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.46 (dd, J=1.6, 9.2 Hz, 1H), 4.39-4.34 (m, 2H), 4.31-4.25 (m, 1H), 4.22-4.18 (m, 2H), 3.59 (s, 3H), 2.85 (s, 4H), 2.37 (s, 3H), 2.10 (s, 3H). MS m/z 503.2 (M+1)+.
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:14]N1C(=O)CCC1=O.O>FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>[I:14][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:8]2[N:9]=[CH:10][CH:11]=[CH:12][N:13]=2)=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1I
Reactant: c1ccc(Oc2ncccn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Ic1ccc(Oc2ncccn2)cc1
Temperature: 25 °C
Yield: 50 %

Procedure:
A mixture of 2-phenoxypyrimidine (int AY) (4.03 g, 0.0234 mol) and N-iodosuccinimide (10.52 g, 0.0468 mol) in trifluoroacetic acid (40 mL) and trifluoroacetic anhydride (8 mL) was heated at reflux for 4 hours. The mixture was allowed to cool to ambient temperature and water (75 mL) was added. The mixture was extracted with three times with 50 mL. The combined organic layers were washed twice with saturated aqueous sodium bicarbonate (50 mL), twice with 10% aqueous sodium thiosulfate (50 mL) and brine (50 mL). The organic layer was dried over magnesium sulfate, filtered and the solvent was removed in vacuo. The crude solid was purified by flash column chromatography on silica gel using n-heptane/ethyl acetate (3:1) as an eluent to give 2-(4-iodophenoxy)pyrimidine as a light yellow solid (3.49 g, 0.0117 mol): 1H NMR (CDCl3, 400 MHz) 8.57 (d, 2H), 7.73 (d, 2H), 7.07 (t, 1H), 6.98 (d 2H); TLC (n-heptane/ethyl acetate=1:1) Rf 0.45.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][C@:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:8])[C:4]1([CH3:18])[CH3:17].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl.O>[C:12]([O:11][C:10]([NH:9][C@:5]1([CH3:8])[CH2:6][CH2:7][C@H:3]([CH2:2][O:1][S:27]([CH3:26])(=[O:29])=[O:28])[C:4]1([CH3:18])[CH3:17])=[O:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@]1(C)CC[C@H](CO)C1(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@]1(C)CC[C@H](COS(C)(=O)=O)C1(C)C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a stirred solution of t-butyl [(1R,3S)-3-(hydroxymethyl)-1,2,2-trimethyl cyclopentyl]carbamate (2.0 g, 7.78 mmol) in 30 mL of dichloromethane maintained at 0° C., triethylamine (5.4 mL, 38.9 mmol) was added. To this reaction mixture, methanesulphonyl chloride (1.91 mL, 23.3 mmol) was added dropwise over a period of 30 minutes and the stirring continued for two hours. Subsequently, the reaction mixture was diluted with dichloromethane and water. The layers were separated and the organic layer was dried over anhydrous Na2SO4, concentrated and dried to give a light yellow colored crude sticky mass, which was purified by column chromatography to furnish methanesulfonic acid (1S,3R)-3-t-butoxycarbonylamino-2,2,3-trimethyl-cyclopentylmethyl ester (2.01 g) in 76% yield as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 0.85 (s, 3H), 1.05 (s, 3H), 1.32 (s, 3H), 1.43 (s, 9H), 1.49 (m, 1H), 1.85-2.04 (m, 3H), 2.20-2.24 (m, 1H), 3.01 (s, 3H), 4.10-4.15 (dd, J=8 & 9.24 Hz, 1H), 4.24-4.29 (dd, J=6.44 & 9.52 Hz, 1H), 4.47 (s, 1H); m/z (M−55): 280.1; [α]D +36.3° (C., 1.0, methanol).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[SiH](C)O[SiH](C)C.C(OC(=O)C)(=O)C.FC(F)(F)S(O[Si](C(C)C)(C(C)C)C(C)C)(=O)=O.[CH2:41]([Si:49]([CH3:55])([CH3:54])[O:50][SiH:51]([CH3:53])[CH3:52])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>[Pt].C1(C)C=CC=CC=1>[CH2:1]([Si:51]([CH3:52])([CH3:53])[O:50][Si:49]([CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([CH3:55])[CH3:54])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[SiH](C)O[Si](C)(C)CCc1ccccc1
Reactant: C=Cc1ccccc1
Agent: [Pt]
Agent: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: C[SiH](C)O[SiH](C)C
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: C[Si](C)(CCc1ccccc1)O[Si](C)(C)CCc1ccccc1
Yield: 58 %

Procedure:
380 mg Of styrene and 240 mg of 1,1,3,3-tetramethyldisiloxane were placed in a glass tube to which 20 μL (21.6 mg) of acetic anhydride and 2 μL (2.3 mg) of triisopropylsilyl trifluoromethanesulfonate (i-Pr3SiOSO2CF3) were added by microsyringe. 5 μL (platinum weight: 0.0017 mg) Of a toluene solution (platinum content: 0.04 wt %) of zero-valent platinum complexed with divinylsiloxane were added to this. The tube was put in a 60° C. oil bath and heated for 8 hours. After cooling, the tube contents were analyzed by gas chromatography, which revealed that the styrene conversion rate was 55%, 1-phenethyl-1,1,3,3-tetramethyldisiloxane had been produced at a yield of 58% (based on 1,1,3,3-tetramethyldisiloxane) and 1,3-bis(phenethyl)-1,1,3,3-tetramethyldisiloxane at a yield of 21%, and the ratio of alpha addition to beta addition of phenethyl groups was 1:49.