Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([N:16]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=1)=[O:5])[CH3:2].Cl.C(=O)([O-])[O-].[NH4+:46].[NH4+]>C(O)C>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([N:16]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:31][O:32][C:33]1[CH:34]=[CH:35][C:36]([C:39](=[NH:46])[NH2:40])=[CH:37][CH:38]=1)=[O:5])[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)Cn1c(COc2ccc(C#N)cc2)nc2cc(N(CCN(C)C)S(=O)(=O)c3ccccc3)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)Cn1c(COc2ccc(C(=N)N)cc2)nc2cc(N(CCN(C)C)S(=O)(=O)c3ccccc3)ccc21

Procedure:
Prepared analogously to Example 1e from 1-ethoxycarbonylmethyl-2-[(4-cyanophenyl)-oxymethyl]-5-[N-(2-dimethylaminoethyl)-benzenesulphonylamino]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:29]=[C:12]3[CH:13]=[C:14]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[N:23]=[CH:22][C:21]=4[C:26](O)=[O:27])=[O:19])[CH:15]=[CH:16][N:11]3[N:10]=2)[CH:6]=[CH:7][CH:8]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:29]=[C:12]3[CH:13]=[C:14]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[N:23]=[CH:22][C:21]=4[C:26]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[O:27])=[O:19])[CH:15]=[CH:16][N:11]3[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: C1COCCN1
Reactant: COc1cccc(-c2nc3cc(NC(=O)c4c(C(=O)O)cnn4C)ccn3n2)c1
Product: COc1cccc(-c2nc3cc(NC(=O)c4c(C(=O)N5CCOCC5)cnn4C)ccn3n2)c1

Procedure:
This compound was prepared in the same manner as described in example 75 starting from 5-[2-(3-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl]-1-methyl-1H-pyrazole-4-carboxylic acid (Example 75, step e) (1.0 g, 2.55 mmol) and morpholine (245 ul, 2.80 mmol). Off-white solid (937 mg, 80%). LC-MS: m/z=462.6 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[C:11](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([O:9][CH3:11])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(O)c(F)cc1Br
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1cc(C)c(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
4-Bromo-2-fluoro-5-methylphenol (40 g, 0.19 mol), cesium carbonate (75 g, 0.23 mol), and iodomethane (15 ml, 0.23 mol) were combined in 100 ml of DMF and stirred at RT for one hour (exothermic). The solution was diluted with ethyl acetate and filtered. The solution was washed with water twice, dried with anhydrous sodium sulfate, filtered, and concentrated. The product was purified via silica gel column chromatography (RediSep 330 g column) using 0-50% ethyl acetate in hexane to afford 1-bromo-5-fluoro-4-methoxy-2-methylbenzene (38 g, 89% yield) as a colorless liquid. No [M+H] peak by LCMS. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.24 (s, 3 H) 3.76 (s, 3 H) 6.73 (d, J=8.80 Hz, 1 H) 7.13 (d, J=10.56 Hz, 1 H)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:6]=[C:5]2[CH2:21][CH2:22][N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:41][CH2:42][CH3:43].CCOC(C)=O>CN(C=O)C>[CH2:41]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:11]([CH:12]([CH3:14])[CH3:13])([CH:18]([CH3:19])[CH3:20])[CH:15]([CH3:16])[CH3:17])[CH:6]=[C:5]2[CH2:21][CH2:22][N:23]1[C:24](=[O:33])[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31]1=[O:32])[CH2:42][CH3:43]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(CCN2C(=O)c3ccccc3C2=O)c2cc(O)ccc21
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1ccc2c(c1)c(CCN1C(=O)c3ccccc3C1=O)cn2[Si](C(C)C)(C(C)C)C(C)C

Procedure:
Combine 2-(2-(5-hydroxy-1-triisopropylsilanyl-1H-indol-3-yl)ethyl)isoindole-1,3-dione (0.7 g, 1.5 mmol), cesium carbonate (1 g, 3 mmol) and 1-iodopropane (0.4 g, 2.3 mmol) in DMF (25 mL) and stir at ambient temperature overnight Pour the reaction mixture into 50% EtOAc in hexanes and wash three times with brine. Dry the organic layer over MgSO4 and concentrate under vacuum to give an oil. Chromatograph the oil on silica gel eluting with 5% EtOAc in hexanes to give the title compound: ISMS 505 (M+1); 1H NMR (CDCl3) 7.80-7.78 (m, 2H), 7.67-7.65 (m, 2H), 7.30-7.27 (d, 1H), 7.12-7.11 (d, 1H), 7.02 (s, 1H), 6.77-6.74 (m, 1H), 4.01-3.96 (m, 4H), 3.12-3.08 (m; 2H), 1.86-1.81 (m, 2H), 1.64-1.57 (m, 3H), 1.08-1.04 (m, 21H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]([F:8])([F:7])[F:6])=O.[CH3:9][O:10][CH2:11][C:12]1[S:16][C:15]([NH2:17])=[N:14][N:13]=1.O>COCCOC>[CH3:9][O:10][CH2:11][C:12]1[S:16][C:15]2=[N:17][C:3]([C:5]([F:8])([F:7])[F:6])=[CH:2][N:14]2[N:13]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: COCc1nnc(N)s1
Solvent: O
Solvent: COCCOC
Product: COCc1nn2cc(C(F)(F)F)nc2s1
Temperature: 80 °C
Yield: 46.7 %

Procedure:
Bromotrifluoroacetone (478 g, 2.5 mol, 1.05 eq) is added on a suspension of 5-(methoxymethyl)-1,3,4-thiadiazol-2-amine a1 (346 g, 2.4 mol, 1 eq) in 1,2-dimethoxyethane (6 l) at 20° C. The reaction mixture is heated to 80° C. until maximum conversion (<24 h). Water (4 l) is added to the reaction mixture at 32° C. and the expected compound crystallized out of the reaction mixture. The crystalline suspension is cooled to 10° C. to complete the crystallization process, filtered and the crystalline precipitate is washed with water (1.5 l) to afford 266 g of pure 2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole a2.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>C(O)CC>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:10][NH2:11])=[N:3][CH:4]=1
Reactant: Fc1ccc(Cl)nc1
Reactant: NN
Solvent: O
Solvent: CCCO
Product: NNc1ccc(F)cn1
Temperature: 200 °C
Yield: 122.1 %

Procedure:
A mixture of 2-chloro-5-fluropyridine (5 g, 0.038 mol) and hydrazine monohydrate (15 ml, 0.32 mol) in n-propanol (40 ml) in a teflon container was purged with argon and heated in a stainless steel bomb at 200° C. for 19 h (magnetic stirring). Evaporation of solvent and excess hydrazine monohydrate in vacuo gave a solid residue (5.9 g) which was dissolved in sodium bicarbonate solution (5%) and extracted with 6×50 ml ethyl acetate. The combined extracts were dried over anhydrous Na2SO4, filtered and evaporated to give an oil (2.9 g) which proved difficult to purify and was therefore used as such in the next step. The crude product consisted of a ternary mixture of the desired product, 2-chloro-5-hydrazinopyridine, and 5-hydrazinopyridine.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:14][O:15][C:16]([C:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17].ON1C2C=CC=CC=2N=N1.[O:35]1[CH:39]=[CH:38][C:37]([C:40](O)=[O:41])=[CH:36]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:14][O:15][C:16]([C:18]1([NH:24][C:40]([C:37]2[CH:38]=[CH:39][O:35][CH:36]=2)=[O:41])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)=[O:17]
Reactant: O=C(O)c1ccoc1
Reactant: COC(=O)C1(N)CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1(NC(=O)c2ccoc2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
105 g (550 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 98.8 g (500 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester hydrochloride, 84.2 g (550 mmol) of 1-hydroxybenzotriazole, 56.0 g (500 mmol) of 3-furancarboxylic acid and 152 g (1.5 mol) of triethylamine in 1000 ml of methylene chloride under ice-cooling. After the mixture was stirred at room temperature overnight, the reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the residue and the mixture was successively washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained crystal was washed with diisopropyl ether to give 114 g (91%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[NH:13][CH2:12][CH2:11][NH:10]2)=[CH:4][CH:3]=1.[Br:14]Br>C(Cl)(Cl)Cl>[BrH:14].[Br:14][C:7]1[CH:6]=[C:5]([N:8]=[C:9]2[NH:10][CH2:11][CH2:12][NH:13]2)[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: BrBr
Reactant: Fc1ccc(N=C2NCCN2)cc1
Solvent: ClC(Cl)Cl
Product: Br
Product: Fc1ccc(N=C2NCCN2)cc1Br

Procedure:
10.75 gm (0.06 mol) of 2-(4-fluoro-phenylimino)-imidazolidine base were dissolved in 210 ml of chloroform, and the solution was dropwisely admixed with bromine at 10° C. while thoroughly stirring. A solid substance precipitated. The mixture was stirred for 30 minutes at 10° C., then suction-filtered, and the filter cake was thoroughly washed with ether and dried, yielding raw 2-(3-bromo-4-fluoro-phenyl-imino)-imidazolidine hydrobromide, m.p. 137°-139° C. The raw hydrobromide was dissolved in water, and the solution was fractionally extracted with ether at gradually increasing pH-values (stepwise alkalization with 2 N sodium hydroxide). The thin layer-chromatographically uniform ether extracts were combined, dried over magnesium sulfate, filtered and acidified with ethereal hydrochloric acid until acid to Congo red. A white substance separated out, which was collected by suction filtration, washed with ether and dried. Yield: 4.12 gm (23.3% of theory) of the hydrochloride, m.p. 182.5° C., Rf -value 0.7 in mobile phase 50 parts benzene, 40 parts dioxane, 5 parts concentrated ammonia, 5 parts ethanol. Carrier: silicagel with fluorescent pigment ZS; visualization; ultraviolet light and potassium platinate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([C:21]2[CH:26]=[CH:25][C:24](OC)=[CH:23][CH:22]=2)[NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[BH4-].[Na+].[CH3:31][OH:32]>O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:31][O:32][C:23]1[CH:22]=[C:21]([CH:10]([NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH3:13])[C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: CO
Reactant: COc1ccc(C(N[C@@H](C)c2cccc(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1cccc(C(N[C@@H](C)c2cccc(F)c2)c2cccc(N)c2)c1

Procedure:
In a similar manner to that described in Example (1b), a solution of N-[(3-nitrophenyl)-(4-methoxyphenyl)methyl]-N-[(S)-1-(3-fluorophenyl)ethyl]amine (2.79 g) [prepared as described in step (a) above] in methanol (50 ml), nickel chloride hexahydrate (3 .49 g) and sodium borohydride (1.17 g) were reacted, and the residue was purified by chromatography through a silica gel column, using mixtures of toluene and ethyl acetate ranging from 8:1 to 5:1 by volume as the eluant, and reverse phase chromatographly through a Lobar column under medium pressure using a 35:65 by volume mixture of acetonitrile and an acetic acid buffer solution (water/acetic acid/triethylamine=1000:2:2) as the eluant, to afford isomer A of the title compound (700 mg) as a yellow oil and isomer B of the title compound (220 mg) as a yellow oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:19]3[CH2:21][CH2:20]3)[C:14]=2[NH2:18])[C:9]1=[O:22])[CH3:7])(=[O:3])[CH3:2].[F:23][C:24]1[CH:25]=[C:26]([CH2:34][C:35](O)=[O:36])[CH:27]=[CH:28][C:29]=1[C:30]([F:33])([F:32])[F:31].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C(Cl)Cl>>[C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:19]3[CH2:20][CH2:21]3)[C:14]=2[NH:18][C:35](=[O:36])[CH2:34][C:26]2[CH:27]=[CH:28][C:29]([C:30]([F:31])([F:32])[F:33])=[C:24]([F:23])[CH:25]=2)[C:9]1=[O:22])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(N)c(C3CC3)ccc2c1=O
Reactant: O=C(O)Cc1ccc(C(F)(F)F)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OC[C@@H](C)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)c(F)c3)c(C3CC3)ccc2c1=O
Temperature: 40 °C

Procedure:
A reaction vial was charged with (R)-2-(5-amino-6-cyclopropyl-1-oxoisoquinolin-2(1H)-yl)propyl acetate (23.0 mg, 0.0000766 mol), 2-(3-fluoro-4-(trifluoromethyl)phenyl)acetic acid (26 mg, 0.00011 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (73 mg, 0.00019 mol), N,N-diisopropylethylamine (33 μL, 0.00019 mol) and methylene chloride (2 mL, 0.03 mol) and the reaction was stirred at 40° C. over night. the solvent was removed under reduced pressure and the residue purified by flash chromatography to afford the product as light yellow solid.
Reaction SMILES: Br[C:2]1[C:7]2[N:8]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([N+:22]([O-:24])=[O:23])[CH:3]=1.[CH2:25]([Sn](CCCC)(CCCC)C=C)[CH2:26]CC>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.O1CCOCC1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([N:8]2[C:7]3[C:2]([CH:25]=[CH2:26])=[CH:3][C:4]([N+:22]([O-:24])=[O:23])=[CH:5][C:6]=3[O:11][C:10]([CH3:13])([CH3:12])[C:9]2=[O:14])=[CH:16][CH:17]=1
Reactant: CC1(C)Oc2cc([N+](=O)[O-])cc(Br)c2N(c2ccc(F)cc2)C1=O
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=Cc1cc([N+](=O)[O-])cc2c1N(c1ccc(F)cc1)C(=O)C(C)(C)O2

Procedure:
A mixture of 5-bromo-4-(4-fluorophenyl)-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (compound obtained in Reference Example 53(6); 100 mg), tributyl(vinyl)tin (78 μL) and tetrakis(triphenylphosphine)palladium(0) (59 mg) and dioxane was refluxed under argon atmosphere for 6 hours. After cooling, the reaction mixture was concentrated in vacuo, and the resultant residue was diluted with acetonitrile and n-hexane. The n-hexane layer was removed from the mixture, and the acetonitrile layer was concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (solvent; n-hexane/ethyl acetate=8/1→4/1) and filtered through NH-silica gel. The filtrate was concentrated in vacuo to give 4-(4-fluorophenyl)-2,2-dimethyl-7-nitro-5-vinyl-2H-1,4-benzoxazin-3(4H)-one (40 mg) as a pale yellow oil.
Reaction SMILES: [C@H]1([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[C:27]([O:30][CH2:31][C:32]3[C:36]5[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=5[O:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:14][CH2:13]2)[C@@H]2N(CCCC2)CCC1.CCN(C(C)C)C(C)C.[C:51]([O:55]C(=O)NC1CCNCC1)([CH3:54])([CH3:53])[CH3:52].C1CN([P+]([O:81]N2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:51]([O:55][C:11]([N:12]1[CH2:13][CH2:14][CH:15]([NH:18][C:19]([C:21]2[NH:22][C:23]3[C:28]([CH:29]=2)=[C:27]([O:30][CH2:31][C:32]2[C:36]4[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=4[O:34][CH:33]=2)[CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:16][CH2:17]1)=[O:81])([CH3:54])([CH3:53])[CH3:52]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4ccc(F)cc34)cccc2[nH]1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc3c(OCc4coc5ccc(F)cc45)cccc3[nH]2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-(5-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (113, see example 60, 160 mg, 0.49 mmol) is dissolved in 1.5 ml of DMF and cooled to 0° C. After addition of Huenigs base (252 ul, 1.5 mmol) the mixture is stirred for 15 min, then piperidin-4-yl-carbamic acid tert-butyl ester (3, 98.5 mg, 0.49 mmol) is added, followed by PyBOP (269 mg, 0.51 mmol). The mixture is stirred at room temperature for 18 h. Then the mixture is diluted with ethyl acetate, washed 1N sodium hydroxide solution and brine. The organic layers are dried over sodium sulfate and evaporated under reduced pressure. The crude product (581 mg) is purified by flash-chromatography (silica gel, cyclohexane/ethyl acetate
Reaction SMILES: Br[C:2]1[C:3](=O)[CH2:4][CH2:5][CH2:6][C:7]=1[O:8]CC.CN(C)C=O.Cl.[CH3:18][CH:19]([CH3:23])[C:20](=[NH:22])[NH2:21].C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[CH3:18][CH:19]([C:20]1[NH:22][C:3]2[CH2:4][CH2:5][CH2:6][C:7](=[O:8])[C:2]=2[N:21]=1)[CH3:23]
Reactant: CCOC1=C(Br)C(=O)CCC1
Reactant: CC(C)C(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)c1nc2c([nH]1)CCCC2=O
Temperature: 50 °C

Procedure:
To 2-bromo-3-(ethyloxy)-2-cyclohexen-1-one (160 g) was added N,N-Dimethylformamide (1000 mL) followed by 2-methylpropanimidamide hydrochloride (107 g) and potassium carbonate (151 g). The suspension was then stirred at 50° C. under nitrogen. After 2.75 hr the mixture was filtered and as much DMF as possible was evaporated off under high vacuum. The residue was partitioned between ethyl acetate (400 ml) and a minimum of aq lithium chloride (120 ml). The aqueous layer was extracted well with ethyl acetate (3×200 ml). The combined organics were washed with brine, filtered to give a small amount of a white solid and the filtrate dried (MgSO4), filtered and evaporated, including high vacuum. This was stirred with TBME (350 ml) then filtered to give a white solid, 16.27 gm. The filtrate from this was evaporated and weighed; this partly solidified overnight. Ether and cyclohexane were added to try and precipitate out more product but the solid was oily. The solution was decanted off and gave a golden oil on evaporation, 77 gm. The oily solid was evaporated: 38 gm, dissolved in DCM and purified by column chromatography (silica cartridge), eluting with 0-100% ethyl acetate in dichloromethane over 10 column volumes. Fractions were evaporated and the resulting solid slurried in ether and collected by filtration: This gave a white solid, 4.0 gm. No solid came out from the aqueous phase overnight. So it was extracted with more ethyl acetate and DCM. The organics were dried and evaporated and gave 69 gm of a beige slurry that was stirred with diethyl ether and filtered to give a white solid, 11.3 gm. The filtrate was combined with aqueous extraction solvents from a previous experiment and purified by column chromatography (silica), eluting with 0-100% ethyl acetate in dichloromethane. All product came through in fractions 1 & 2 so they were combined and washed with aq LiCl, dried and re-evaporated to a beige slurry, 46.4 gm, that was stirred in ether and filtered to give a white solid, 5.85 gm. Because all the batches were of the same purity, they were combined: This gave the title compound, a white solid, 37.42 gm.
Reaction SMILES: [CH3:1][Li].[Si:3]([O:10][CH2:11][C@H:12]1[C@@H:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[N:13]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[Cl-].N.[OH-].N>CCOCC>[Si:3]([O:10][CH2:11][C@@H:12]([NH:13][C:25](=[O:26])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C@H:14]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)[CH3:1])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: [Li]C
Reactant: CC(C)(C)OC(=O)N1[C@H](c2ccc(C(F)(F)F)cc2)[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: N
Agent: [Cl-]
Agent: [OH-]
Solvent: CCOCC
Product: C[C@@H](c1ccc(C(F)(F)F)cc1)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
To a stirred slurry of cuprous iodide (7.9 g, 42 mmol) in 150 mL ether at 0° C. was added methyllithium (1.6 M solution in diethyl ether (52 mL, 83 mmol)). The mixture was stirred at this temperature for 20 minutes. A solution of (2R,3R)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-3-(4-(trifluoromethyl)phenyl)aziridine 1-carboxylate (6.00 g, 14 mmol) in 150 mL ether was added via cannula to the lithium dimethylcuprate solution. The mixture was stirred at 0° C. and monitored by TLC. When no starting material could be detected (ca. 7 hours), 250 mL of an 8:1 mixture of saturated aqueous ammonia chloride and ammonia hydroxide (28-30% in water) was added to the reaction. The resulting reaction mixture was extracted with diethyl ether (2×300 mL). The combined organic layers were washed twice with brine and dried over sodium sulfate. The crude product was then chromatographed eluting with 3% EtOAc in hexane. After removing the solvent, the desired product was obtained as a colorless oil (2.0 g, yield=32%). 1H NMR (400 MHz, CD3OD) δ ppm 0.09 (s, 6H) 0.90-0.96 (m, 9H) 1.25-1.33 (m, 12H) 3.00-3.11 (m, 1H) 3.68-3.80 (m, 3H) 7.43 (d, J=8.02 Hz, 2H) 7.56 (d, J=8.02 Hz, 2H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Si:11]([O:18][CH2:19][C:20]1([CH2:23][OH:24])[CH2:22][CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>C(Cl)Cl>[Si:11]([O:18][CH2:19][C:20]1([CH:23]=[O:24])[CH2:21][CH2:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)OCC1(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCC1(C=O)CC1
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 65.6 %

Procedure:
To a stirred solution of DMSO (6.9 mL, 0.097 mol) in anhydrous DCM (90 mL) at −70° C. was added oxalyl chloride (4.20 mL, 0.0486 mol). After stirring for 10 min. at −70° C., a solution of [1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopropyl]methanol (7.011 g, 0.03240 mol) in anhydrous DCM (30 mL) was added via cannula. The resulting milky mixture was slowly warmed to −55° C. over 45 min. DIPEA (34.0 mL, 0.194 mol) was added. The resulting mixture was stirred for 5 min. at −55° C., and then the cooling bath was removed and the reaction mixture was allowed to warm to RT. The reaction was then quenched with saturated aqueous NaHCO3 (150 mL) and extracted with DCM (2×). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by Combiflash chromatography eluting with 0-10% EtOAc/hexanes to afford the desired product as a colorless oil (4.558 g, 66% yield).
Reaction SMILES: [CH3:1][SiH:2]1[O:9][SiH:8]([CH3:10])[O:7][SiH:6]([CH3:11])[O:5][SiH:4]([CH3:12])[O:3]1.[C:13]([O:17][CH2:18][CH2:19][OH:20])(=[O:16])[CH:14]=[CH2:15].C1C=CC=CC=1>O>[C:13]([O:17][CH2:18][CH2:19][O:20][Si:8]1([CH3:10])[O:9][SiH:2]([CH3:1])[O:3][SiH:4]([CH3:12])[O:5][SiH:6]([CH3:11])[O:7]1)(=[O:16])[CH:14]=[CH2:15]
Reactant: C=CC(=O)OCCO
Reactant: C[SiH]1O[SiH](C)O[SiH](C)O[SiH](C)O1
Solvent: c1ccccc1
Solvent: O
Product: C=CC(=O)OCCO[Si]1(C)O[SiH](C)O[SiH](C)O[SiH](C)O1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixed solution containing 1 M of 2,4,6,8-tetramethylcyclotetrasiloxane and 0.01 g of Zn(CH3CO2)2 was slowly added 1 M of 2-hydroxyethyl acrylate. The resulting mixture was stirred for 12 hours at a room temperature. Thereafter, 200 mL of benzene and 200 mL of cold water were added. The organic layer was separated, washed with 200 mL of cold water, dried over MgSO4, filtered, and concentrated by distillation to provide the title compound of Formula 1A (yield: 97%).