Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:9]#[N:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:22][C:21]([CH3:23])=[N:20][C:19]=2[C:24](O)=[O:25])=[CH:14][CH:13]=1>>[NH2:10][CH2:9][C@H:4]1[C@@H:3]([O:2][CH3:1])[CH2:8][CH2:7][CH2:6][N:5]1[C:24]([C:19]1[N:20]=[C:21]([CH3:23])[S:22][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=1)=[O:25]
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: COc1cccnc1C#N
Product: CO[C@H]1CCCN(C(=O)c2nc(C)sc2-c2ccc(F)cc2)[C@H]1CN

Procedure:
The title compound was synthesized following the same general protocol as described in Example 11 using 3-methoxypicolinonitrile and 5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid. MS (ESI) 464.4 (M+H)
Reaction SMILES: [CH3:1][Si:2]([CH3:18])([CH3:17])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6]2.[CH3:19][C:20]1[CH:21]=[C:22]([CH2:26]O)[CH:23]=[CH:24][CH:25]=1.C(C=P(CCCC)(CCCC)CCCC)#N>>[CH3:1][Si:2]([CH3:17])([CH3:18])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1)[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6]2
Reactant: Cc1cccc(CO)c1
Reactant: CCOC(=O)c1cc2cc([Si](C)(C)C)ccc2[nH]1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Product: CCOC(=O)c1cc2cc([Si](C)(C)C)ccc2n1Cc1cccc(C)c1

Procedure:
This compound was prepared according to a process similar to that described in step 5.1 by reacting ethyl 5-trimethylsilyl-1H-indole-2-carboxylate prepared according to the process described in step 10.4 with (3-methylphenyl)methanol in the presence of (cyanomethylene)tributylphosphorane (CMBP). The crude reaction product is then purified by flash chromatography on a column of silica gel to give the expected product.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(S(F)(F)[F:25])CC)C>ClCCl>[C:1]1([CH2:7][CH2:8][S:9][CH:11]([F:25])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=S(CCc1ccccc1)CCc1ccccc1
Solvent: ClCCl
Product: FC(Cc1ccccc1)SCCc1ccccc1

Procedure:
According to the procedure of McCarthy et. al. (J. Amer. Chem. Soc. 1985, 107, 735), the resultant compound of Example 2 was treated with diethylaminosulfur trifluoride in dichloromethane to give the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])[C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20]([NH:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:21])[C:9]2[C:10]([CH3:16])=[CH:11][CH:12]=[CH:13][C:14]=2[CH3:15])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1cccc(C)c1N(CCCC(=O)O)C(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)CN
Product: CCOC(=O)CNC(=O)CCCN(C(=O)c1ccc(Cl)cc1)c1c(C)cccc1C

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyric acid and ethyl glycinate and suitable processing produces ethyl N-[N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyryl]glycinate (oil), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyryl]glycine (M.P. 141° to 142°).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:23])[N:7]=1)=[O:5])[CH3:2].Br[C:25]1[CH:26]=[N:27][N:28]([CH2:30][CH2:31][CH3:32])[CH:29]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:25]3[CH:26]=[N:27][N:28]([CH2:30][CH2:31][CH3:32])[CH:29]=3)[C:14]=2[CH3:23])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)n1
Reactant: CCCn1cc(Br)cn1
Product: CCCn1cc(-n2c(C)c(Sc3cccc(C(=O)OCC)n3)c3ccc(Cl)cc32)cn1

Procedure:
Prepared according to the procedure described in Example 9, Step 4, using the following starting materials: 6-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-pyridine-2-carboxylic acid ethyl ester and 4-bromo-1-propyl-1H-pyrazole.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[OH:24])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:32](Br)[C:33]#[CH:34].C1(C)C=CC=CC=1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[O:24][CH2:34][C:33]#[CH:32])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:5])[CH3:2]
Reactant: C#CCBr
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2O)Cc2ccccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C#CCOc1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1

Procedure:
A 100 mL round bottom flask containing the 2-(hydroxy-3-methyl-benzoyl)-indan-2-carboxylic acid ethyl ester (3) (0.29 g 0.855 mmol) is charged with DMF (4 mL) and a stirring bar is added. After dissolution of the starting material, K2SO4 (0.3 g, 2.17 mmol) is added followed by a solution of propargyl bromide in toluene (11.59 M, 240 μL, 2.78 mmol). After stirring for 62 h tlc analysis (silica, 1:1 EtOAc/heptanes) indicates that the starting material had been consumed. The material is cleanly converted to a UV positive spot with a slightly lower Rf. The reaction is diluted with EtOAc (80 mL) and filtered through a pad of Celite. The filtrate is transferred to a reparatory funnel. This is washed repeatedly with a saturated aqueous solution of NaHCO3 (2×50 mL) and brine (50 mL), dried over Na2SO4, filtered and evaporated in vacuo to yield 2.09 g of a light brown oil. This is purified (silica, 40 g ISCO column 10% EtOAc in heptanes for 3 column volumes followed by a linear gradient to 50% EtOAc in heptanes for 10 column volumes). 17 mL fractions of UV positive eluent are collected. Fractions 4 through 10 are combined, evaporated in vacuo and pumped to constant weight to give 0.21 g of white solid.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([CH2:26][CH2:27][C:28]([OH:30])=O)=[N:16][N:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:18]=2)=[CH:10][CH:9]=1>C(OCC)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([CH2:26][CH2:27][C:28]([Cl:2])=[O:30])=[N:16][N:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:18]=2)=[CH:10][CH:9]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(O)CCc1nn(-c2ccc(F)cc2)cc1-c1ccc(Cl)cc1
Solvent: CCOCC
Product: O=C(Cl)CCc1nn(-c2ccc(F)cc2)cc1-c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 92.4 %

Procedure:
At 0° C., 1.3 g of phosphorus pentachloride is added in incremental portions to a mixture of 1.9 g of 3-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]propionic acid in 60 ml of diethyl ether; the mixture is agitated for 3 hours, then concentrated, and the residue recrystallized from petroleum ether, thus obtaining 1.85 g of 3-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]propionic acid chloride, mp 111° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].C1C=CC2N(O)N=NC=2C=1.[C:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][C:28]=1[OH:36])(=[O:26])[CH3:25].C(Cl)CCl>CN(C=O)C>[CH3:2][O:3][C:4]([C:6]1([NH:13][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([C:24](=[O:26])[CH3:25])=[C:28]([OH:36])[CH:29]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)=[O:5]
Reactant: COC(=O)C1(N)CCCCCC1
Reactant: CC(=O)c1ccc(C(=O)O)cc1O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)C1(NC(=O)c2ccc(C(C)=O)c(O)c2)CCCCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-Amino-cycloheptanecarboxylic acid methyl ester hydrochloride (968 mg, 4.66 mmol), HOBT (105 mg, 0.78 mmol) and 4-acetyl-3-hydroxy-benzoic acid (700 mg, 3.89 mmol) were dissolved in DMF (5 ml). EDIA (3.01 g, 23.3 mmol) and EDC were added and the mixture was stirred at room temperature for 72 h. Then the mixture was partitioned between EA and saturated sodium chloride solution, the aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was purified by RP HPLC (water/ACN gradient) to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:9]([CH2:18][NH2:19])[O:8][C:7]=2[CH:20]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].Cl>N1C=CC=CC=1.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:9]([CH2:18][NH:19][C:21](=[O:23])[CH3:22])[O:8][C:7]=2[CH:20]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)OC(CN)=C(c1ccccc1)O2
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc2c(c1)OC(CNC(C)=O)=C(c1ccccc1)O2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.2 g (0.74 mmol) of the amine obtained in Step C is dissolved in 3 ml of anhydrous pyridine; the solution is then cooled to 0° C. After addition of 0.085 ml (0.89 mmol) of acetic anhydride, the reaction medium is stirred for 1 hour at 0° C. The solution is then diluted with dichloromethane and then acidified with a hydrochloric acid solution (1N). The aqueous phase is extracted with dichloromethane; the organic phase is then dried over magnesium sulphate. After evaporation of the solvent in vacuo, the residue obtained is purified on a silica column (eluant:AcOEt/PE:60/40) to yield the title amide in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([CH3:11])[CH2:9][OH:10])=[C:6]([Cl:12])[N:5]=[CH:4][N:3]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:12][C:6]1[C:7]([CH:8]([CH3:11])[CH2:9][O:10][S:14]([CH3:13])(=[O:16])=[O:15])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(CO)c1c(Cl)ncnc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(COS(C)(=O)=O)c1c(Cl)ncnc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
To a solution of 2-(4,6-Dichloro-pyrimidin-5-yl)-propan-1-ol (0.40 g, 1.93 mmol) in DCM (40 mL) were added MsCl (0.50 g, 4.36 mmol), TEA (1 mL) and catalytic amount of DMAP. The mixture was stirred at room temperature for 2 hours. The solvent was removed and the residue was subject to column chromatography, eluted by hexane/ethyl acetate (4:1) to give methanesulfonic acid 2-(4,6-dichloro-pyrimidin-5-yl)-propyl ester (0.54 g, 98%). 1H NMR (CDCl3, 400 MHz) δ 8.68 (s, 1H), 4.74 (m, 1H), 4.55 (m, 1H), 4.14 (m, 1H), 2.99 (s, 3H), 1.49 (dd, J=7.2 Hz, J=1.2 Hz, 3H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH3:17][N:18]([CH3:20])[CH:19]=[N:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: COC(OC)N(C)C
Product: CN(C)C=NC1CCN(Cc2ccccc2)CC1
Yield: 83.2 %

Procedure:
The starting 4-amino-1-benzylpiperidine from Part B above (15.0 g, 78.8 mmol) is treated with dimethylformamide dimethylacetal (18.78 g, 157.6 mmol) and refluxed for 2 hours. The solution is permitted to cool overnight, then concentrated in vacuo to the product (15.5 g of oil, 83.2% yield), which solidifies on standing. A small portion crystallizes from hexane to afford colorless needles with a melting point of 61°-65° C.: NMR (CDCl3 δ) 7.28, 3.49, 2.80, and 1.75-3.0; mass spectral molecular ion peak at m/e 245, with abundant fragment ions at m/e 200, 173, 172, 154, and 91.
Reaction SMILES: N12CCCN=C1CCCCC2.CS(O[CH2:17][C@@H:18]1[O:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH2:31][CH2:32][O:33][CH2:34][CH:35]=3)=[C:26]([F:36])[CH:25]=2)[CH2:19]1)(=O)=O.CS(Cl)(=O)=O.[SH:42][C:43]1[NH:44][CH:45]=[CH:46][N:47]=1>O1CCOCC1>[NH:44]1[CH:45]=[CH:46][N:47]=[C:43]1[S:42][CH2:17][C@@H:18]1[O:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH2:31][CH2:32][O:33][CH2:34][CH:35]=3)=[C:26]([F:36])[CH:25]=2)[CH2:19]1
Reactant: Sc1ncc[nH]1
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(C3=CCOCC3)c(F)c2)C(=O)O1
Agent: CS(=O)(=O)Cl
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1O[C@@H](CSc2ncc[nH]2)CN1c1ccc(C2=CCOCC2)c(F)c1
Temperature: 60 °C
Yield: 30 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.1 ml, 0.674 mmol) was added to a stirred suspension of 5(R)-methanesulfonyloxymethyl 3-(4-[3,6-dihydro-(2H)-pyran-4-yl]-3-fluorophenyl)oxazolidin-2-one (prepared from the 5(R)-hydroxymethyl compound (WO97/09328) by reaction with methylsulfonyl chloride) (0.25 g, 0.674 mmol) and 2-mercaptoimidazole (0.067 g, 0.674 mmol) in dioxan (2 ml) under nitrogen. The mixture was heated at 60° C. for 4 hours and evaporated. The residue was purified by column chromatography, eluting first with 2% MeOH/EtOAc and then with 4% MeOH/EtOAc to give the title product as a solid (0.077 g, 30%); mp 178-179° C. (dec.) MS: 476 (MH+); NMR: 2.39 (2H, bs); 3.42 (2H, m); 3.79 (2H, t); 3.86 (1H, m); 4.19 (3H, m); 4.89 (1H, m); 6.07 (1H, s); 7.04 (2H, s); 7.26 (1H, dd); 7.38 (1H, t); 7.46 (1H, d).
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:21][C@@:20]2([CH3:22])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[C:18](=O)[CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[CH2:24])[CH2:6][C@@H:5]1[OH:25])[CH3:2].Cl.[NH2:27][OH:28]>C(O)C.[OH-].[Na+]>[CH2:1]([O:3][C@H:4]1[CH2:21][C@@:20]2([CH3:22])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[C:18](=[N:27][OH:28])[CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[CH2:24])[CH2:6][C@@H:5]1[OH:25])[CH3:2]
Reactant: C=C1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCC)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=C1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCC)C[C@]4(C)[C@H]3C(=NO)C[C@]12C
Yield: 76.7 %

Procedure:
A solution of 2β-ethoxy-3α-hydroxy-17-methylene-5α-androstan-11-one (1.75 g) in ethanol (50 ml) was added to a mixture of hydroxylamine hydrochloride (3.6 g) in 50% sodium hydroxide solution (14 ml) and the resulting suspension was stirred and refluxed for 35 hours. Most of the solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate and water. Evaporation of the washed organic layer and crystallization of the residue from ethyl acetate afford the title compound (1.4 g), m.p. 97°-99°, [α]D +44.1°.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:20][NH2:21]>C1(C)C=CC=CC=1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C@H:8]2[CH2:9][CH2:10][C@H:5]([C:3]([NH:20][NH2:21])=[O:2])[CH2:6][CH2:7]2)=[CH:13][CH:14]=1
Reactant: COC(=O)[C@H]1CC[C@H](Oc2ccc(F)cc2)CC1
Reactant: NN
Solvent: O
Solvent: Cc1ccccc1
Product: NNC(=O)[C@H]1CC[C@H](Oc2ccc(F)cc2)CC1
Temperature: 120 °C

Procedure:
A mixture of trans-4-(4-fluoro-phenoxy)-cyclohexanecarboxylic acid methyl ester (0.23 g, 0.93 mmol) and hydrazine hydrate (0.046 g, 0.91 mmol) was heated at 120° C. for 3.5 h. After cooling to room temperature the reaction mixture was suspended in toluene (70 ml). After evaporation of the solvent, the residue was suspended in toluene (70 ml) again. The solvent was evaporated and the residue was dried in high vacuo (1-2 mbar) to give the crude title compound (0.22 g, 96%) as white solid, which was used in the next step without further purification. MS m/e: 253 (M+H+).
Reaction SMILES: Br[C:2]1[C:16]([CH3:17])=[CH:15][C:5]([O:6][CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([O:18][CH3:19])[CH:3]=1.C([Li])CCC.[B:25](OC)([O:28]C)[O:26]C>C1COCC1>[CH3:19][O:18][C:4]1[C:5]([O:6][CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:15][C:16]([CH3:17])=[C:2]([B:25]([OH:28])[OH:26])[CH:3]=1
Reactant: COc1cc(Br)c(C)cc1OCOCC[Si](C)(C)C
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(B(O)O)c(C)cc1OCOCC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
[2-(4-Bromo-2-methoxy-5-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane (2.6 g, 7.5 mmol) was stirred in dry THF (10 mL) at −78° C. under argon. n-Butyllithium (3.75 mL, 2.5 M in hexanes, 9.36 mmol) was added dropwise, and the reaction stirred for 30 min before it was transferred via cannula to a flask of trimethyl borate (8.4 mL, 75 mmol) in THF (15 mL), which was also stirring at −78° C. under argon. After addition was complete, the reaction stirred 30 min at −78° C. and then 30 min while warming to 0° C. It was then quenched with H2O (20 mL), acidified with 0.1 N HCl, and extracted with ethyl acetate (2×25 mL). Organics were washed with brine (20 mL), dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography (20% to 50% ethyl acetate/hexanes) gave 1.11 g (47%) of 5-methoxy-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronic acid as a white solid. 1NMR (300 MHz, CDCl3) δ 7.78 (s, 1H), 7.10 (s, 1H), 5.36 (s, 2H), 3.93 (s, 3H), 3.83 (t, 2H, J=8.4 Hz), 2.79 (s, 3H), 0.98 (t, 2H, J=8.4 Hz), 0.01 (s, 9H). Anal. (C14H25BO5Si—H2O) C, H. Calculated: C, 57.15; H, 7.88. Found: C, 56.89; H, 7.87.
Reaction SMILES: O.[OH-].[Li+].[F:4][CH:5]([F:33])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([O:21][C:22]2[CH:27]=[N:26][C:25]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])=[CH:24][N:23]=2)[CH:20]=1)[C:14]([O:16]C)=[O:15])[CH3:9]>O.C1COCC1>[F:33][CH:5]([F:4])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([O:21][C:22]2[CH:27]=[N:26][C:25]([C:28](=[O:32])[N:29]([CH3:30])[CH3:31])=[CH:24][N:23]=2)[CH:20]=1)[C:14]([OH:16])=[O:15])[CH3:9]
Reactant: COC(=O)c1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(O[C@@H](C)COC(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](COC(F)F)Oc1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.3 %

Procedure:
Lithium hydroxide monohydrate (45 mg, 1.06 mol) in water (5 mL) was added to a solution of methyl 3-[(2S)-1-(difluoromethoxy)propan-2-yl]oxy-5-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-benzoate (0.3 g, 0.71 mmol) in THF (10 mL) and stirred at RT for 20 hours. The THF was removed in vacuo and the aqueous layer was washed with ethyl acetate (50 mL) to remove any impurities. The aqueous layer was acidified and extracted into ethyl acetate (2×50 mL) then the combined organics washed with brine (50 mL), dried (MgSO4) and the solvent removed in vacuo to give the desired compound (0.22 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([N:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=3[S:13]2)[CH2:11][CH2:10][CH2:9][CH2:8]1.Br[CH2:24][C:25]1[CH:26]=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([O:39][CH3:40])=[O:38])=[C:33]([Cl:41])[CH:32]=2)[CH:28]=[CH:29][CH:30]=1>CC#N>[Cl:41][C:33]1[CH:32]=[C:31]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][O:22][C:20]3[CH:19]=[CH:18][C:15]4[C:16](=[O:17])[N:12]([CH:7]5[CH2:8][CH2:9][CH2:10][CH2:11]5)[S:13][C:14]=4[CH:21]=3)[CH:26]=2)[CH:36]=[CH:35][C:34]=1[C:37]([O:39][CH3:40])=[O:38]
Reactant: O=c1c2ccc(O)cc2sn1C1CCCC1
Reactant: COC(=O)c1ccc(-c2cccc(CBr)c2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(-c2cccc(COc3ccc4c(=O)n(C5CCCC5)sc4c3)c2)cc1Cl
Temperature: 80 °C
Reaction time: 12 h
Yield: 99.9 %

Procedure:
Potassium carbonate (0.052 g, 0.38 mmol) was added to a solution of 2-cyclopentyl-6-hydroxybenzo[d]isothiazol-3(2H)-one (0.075 g, 0.32 mmol) and methyl 3′-(bromomethyl)-3-chlorobiphenyl-4-carboxylate (0.129 g, 0.38 mmol) in CH3CN (5 mL). After stirring for 12 h at 80° C., the organic phase was evaporated under reduced pressure and the crude material was partitioned between water and CH2Cl2. The aqueous layer was extracted with CH2Cl2 (3×15 mL). The organic layer was dried over Na2SO4 and evaporated to give methyl 3-chloro-3′-((2-cyclopentyl-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yloxy)methyl)biphenyl-4-carboxylate (0.158 g, quantitative yield). The crude product was used for the next step without further purification. LC-MS (ESI) Calcd for C27H24NO2S [M+H]+: 494.11. Found: 494.00.
Reaction SMILES: [H-].[Na+].Br[C:4]1[C:9]([NH:10][C:11]([C:13]2[C:14]([NH:19][CH2:20][CH3:21])=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])=[C:8]([CH3:22])[CH:7]=[C:6]([O:23][CH3:24])[N:5]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:20]([N:19]1[C:14]2[N:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:11](=[O:12])[NH:10][C:9]2[C:8]([CH3:22])=[CH:7][C:6]([O:23][CH3:24])=[N:5][C:4]1=2)[CH3:21]
Reactant: CCNc1ncccc1C(=O)Nc1c(C)cc(OC)nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCN1c2ncccc2C(=O)Nc2c(C)cc(OC)nc21
Yield: 47.6 %

Procedure:
Sodium hydride (0.14 g of a 50% dispersion in mineral oil) was added to a solution of N-(2-bromo- 6-methoxy-4-methyl-3-pyridinyl)-2-ethylamino-3-pyridinecarboxamide (0.54 g) in pyridine (4 ml), and the resulting mixture was refluxed for 1.5 hours. The cooled mixture was diluted with ethyl acetate, washed with water, and the organic phase was dried (anhydrous magnesium sulfate) and concentrated. The residue was washed with diisopropyl ether and hot ethyl acetate, and then crystallized from ethanol to provide 0.2 g of 5,11-dihydro-11-ethyl-2-methoxy-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one m.p. 249°-251° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH2:4][CH2:5][NH:6][CH2:7][CH2:8][C:9]=1[C:10]#[N:11].[CH2:12](I)[CH3:13]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:12]([N:6]1[CH2:7][CH2:8][C:9]([C:10]#[N:11])=[C:3]([Cl:2])[CH2:4][CH2:5]1)[CH3:13]
Reactant: CCI
Reactant: N#CC1=C(Cl)CCNCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1CCC(Cl)=C(C#N)CC1
Reaction time: 8 h

Procedure:
7.1 gm (0.037 mol) of 4-chloro-5-cyano-2,3,6,7-tetrahydro-1H-azepine hydrochloride were dissolved in 170 ml of chloroform by addition of 28.5 ml of triethylamine. Then, 8.6 gm (0.055 mol)=4.9 ml of ethyl iodide were added dropwise at the boiling point, while stirring, and the mixture was refluxed for 4 hours. To complete the reaction, another 10 ml of triethylamine and 2.5 ml of ethyl iodide were added, and the mixture was boiled further. After a total of 10 hours the reaction was finished. After standing overnight, the mixture was concentrated by evaporation in vacuo. The residue was chromatographed on a silica-gel column (chloroform/methyl alcohol/ammonia=9:1:0.1). After the corresponding fractions had been concentrated by evaporation, the mixture was evaporated in vacuo.
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][C:7]1[CH:8]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[C:11]([CH3:13])[CH:12]=1.[B:20](OC)([O:23]C)[O:21]C.Cl>O1CCCC1>[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]=1[B:20]([OH:23])[OH:21]
Reactant: Cc1cc(C)cc(-c2ccccc2)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc(C)c(B(O)O)c(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
tert-Butyllithium (1.7 M solution in hexanes, 36.2 ml, 62.6 mmol) is added dropwise to a solution of 3,5-dimethylbiphenyl (7.27 g; 28 mmol) in dry tetrahydrofuran (150 ml) at −78° C. and stirred under an atmosphere of nitrogen for 30 minutes. Trimethyl borate (9.54 ml; 84 mmol) is added and the resulting mixture is stirred at −78° C. for 30 min and then allowed to warm to room temperature. The reaction mixture is acidified with aqueous hydrochloric acid and extracted with ether (2×150 ml). The organic layers are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo to give a yellow solid. The crude product is triturated with iso-hexane and filtered to give 3,5-dimethylbiphenylboronic acid (5.89 g) as a white powder.