Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:15][C:14](=[O:16])[NH:13][CH2:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:34][O:35][C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([O:46][CH3:47])[C:43]=1[O:44][CH3:45])[CH2:39]Cl.C(OCC)(=O)C.CCCCCC>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:47][O:46][C:42]1[CH:41]=[C:38]([CH:37]=[C:36]([O:35][CH3:34])[C:43]=1[O:44][CH3:45])[CH2:39][N:13]1[C:14](=[O:16])[CH2:15][C:11]([CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12]1
Reactant: CC(C)(C)[Si](C)(C)OCCC1(Cc2ccccc2)CNC(=O)C1
Reactant: COc1cc(CCl)cc(OC)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(CN2CC(CCO[Si](C)(C)C(C)(C)C)(Cc3ccccc3)CC2=O)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Combine 3-(2-(t-butyldimethylsilyloxy)ethyl)-3-(phenylmethyl)-5-oxopyrrolidine (0.13 g, 0.38 mmol) and tetrahydrofuran (2 mL). Cool to −78° C. using a dry-ice/acetone bath. Add a solution of potassium bis(trimethylsilyl)amide (0.76 mL, 0.5 M in toluene, 0.38 mmol). After 30 minutes, add a solution of 3,4,5-trimethoxybenzyl chloride (0.08 g, 0.38 mmol) in tetrahydrofuran (1 mL). Warm to ambient temperature and add tetrabutylammonium bromide (0.01 g). Heat to reflux. After 12 hours, cool the reaction mixture and partition between water and ethyl acetate. Separate the aqueous layer and extract twice with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 1/4 ethyl acetate/hexane to give the title compound: Rf=0.43 (silica gel, 1/1 ethyl acetate/hexane).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH2:20])=[N:8][C:6]=2[N:7]=1.[CH:21]([N:24]=[C:25]=[O:26])([CH3:23])[CH3:22].N>C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH:20][C:25]([NH:24][CH:21]([CH3:23])[CH3:22])=[O:26])=[N:8][C:6]=2[N:7]=1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Reactant: CC(C)N=C=O
Agent: C
Agent: N
Product: CC(C)NC(=O)Nc1nc2nc(N)ncc2cc1-c1c(Cl)cccc1Cl

Procedure:
The title compound was prepared from 0.5 g of 6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 1 and 0.172 mL of isopropyl isocyanate according to Example 2. The product was purified by MPLC eluting with a gradient of CHCl3 :EtOAc (1:1) to afford the pure product; mp 184-188° C., CIMS (1% ammonia in methane) m/z (relative intensity) 391 (MH+, 16), 393 (MH+ +2, 11), 306 (100).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8](/[CH:12]=[CH:13]\[O:14][CH2:15]C)=[CH:7][N:6]=1)=[O:4].CO.[C:19]([O-])(O)=[O:20].[Na+]>Cl>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([CH2:12][CH:13]([O:14][CH3:15])[O:20][CH3:19])=[CH:7][N:6]=1)=[O:4]
Reactant: CCO/C=C\c1cnc(C(=O)OC)c(N)n1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ncc(CC(OC)OC)nc1N

Procedure:
A solution of 3-amino-5-((Z)-2-ethoxy-vinyl)-pyrazine-2-carboxylic acid methyl ester (220 mg, 0.986 mmol) in 3M HCl in MeOH (210 μl, 6.90 mmol) was heated at 55° C. over night. A solution of 10% of NaHCO3 was added the mixture was extracted with EtOAc. The combined organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure to obtain a brown solid (141 mg). The crude material was directly used in the next step without further purification.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:32]=[CH:33][CH:34]=3)[CH2:19][N:20]3[C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([C:29]([OH:31])=O)[C:23]=4[CH:22]=[CH:21]3)=[O:15])=[C:9]([C:35]3[CH:40]=[C:39]([C:41](=[O:54])[NH:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:53])([F:52])[F:51])[CH:45]=4)[CH:38]=[CH:37][N:36]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][C:67]([OH:69])=[O:68].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[O:31]=[C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:23]=1[CH:22]=[CH:21][N:20]2[CH2:19][C:18]1[CH:32]=[CH:33][CH:34]=[C:16]([C:14](=[O:15])[NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:8][C:9]=2[C:35]2[CH:40]=[C:39]([C:41](=[O:54])[NH:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:51])([F:52])[F:53])[CH:45]=3)[CH:38]=[CH:37][N:36]=2)[CH:17]=1)[NH:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][C:67]([OH:69])=[O:68]
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(Cn3ccc4c(C(=O)O)cccc43)c2)c1
Reactant: NCCOCCOCCOCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CCOCCOCCOCCNC(=O)c1cccc2c1ccn2Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 1 h
Yield: 36.5 %

Procedure:
A mixture of 3 mg of 1-(3-((4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)-benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzyl)-1H-indole-4-carboxylic acid 9.1, 1.7 mg of 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoic acid, and 2.5 mg of HATU in 300 μL of DMF was treated with 1.5 μL of diisopropylethylamine. After 2 h the solvent was evaporated and the residue was partitioned between ethyl acetate and water. The aqueous phase was washed with ethyl acetate, and the combined organic extracts were washed with brine and dried (Na2SO4). The solvent was evaporated and a fraction of the product was dissolved in 1:1 dichloromethane/TFA. After stirring for 1 h the solvent was evaporated and the residue was purified by reverse phase HPLC eluting with 0.05% TFA in a water/acetonitrile gradient to yield 1.4 mg of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 9.57 (t, J=5.7 Hz, 1H), 8.98 (d, J=5.1 Hz, 1H), 8.51 (d, J=8.7 Hz, 1H), 8.40 (s, 1H), 7.93 (s, 1H), 7.89 (d, J=5.1 Hz, 1H), 7.78 (d, J=7.4 Hz, 1H), 7.72 (s, 1H), 7.65 (m, 2H), 7.60-7.52 (m, 3H), 7.48 (t, J=7.7 Hz, 1H), 7.24-7.14 (m, 3H), 7.03-6.94 (m, 1H), 4.64 (d, J=5.8 Hz, 2H), 4.36 (s, 2H), 3.47 (s, 4H), 2.15 (t, J=7.3 Hz, 2H), 1.83 (br, 4H), 1.81-1.67 (m, 2H), 1.64 (br, 2H). MS (ES, m/z) 935.32 [M+H]+
Reaction SMILES: [F:1]/[C:2](=[C:8](\[CH3:19])/[CH:9]=[CH:10]/[C:11]1[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:12]=1[CH3:18])/[C:3](OCC)=[O:4].[H-].C([Al+]CC(C)C)C(C)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)C>[F:1]/[C:2](=[C:8](\[CH3:19])/[CH:9]=[CH:10]/[C:11]1[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:12]=1[CH3:18])/[CH2:3][OH:4]
Reactant: CCOC(=O)/C(F)=C(C)\C=C\c1c(C)sc(C)c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: CCOCC
Product: CC(/C=C/c1c(C)sc(C)c1C)=C(\F)CO
Temperature: -45 °C

Procedure:
A solution of 6.5 g. (23 mmol) of ethyl (2E,4E)-2-fluoro-3-methyl-5-(2,4,5-trimethyl-3-thienyl)-2,4-pentadienoate in diethyl ether was stirred under argon and cooled to -45° C. Diisobutylaluminum hydride (DIBAH) was added slowly until three equivalents had been added and no starting ester remained. Five ml. of a saturated solution of sodium sulfate was added at -10° C. and the mixture was allowed to come to 30° C. Filtration through Celite and subsequent washing of the residue with methylene chloride gave a clear yellow solution of 2E,4E-2-fluoro-3-methyl-5-(2,4,5-trimethyl-3-thienyl)-2,4-pentadien-1-ol which was carried on to the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([C:19]([F:35])([F:34])[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32]Cl)=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)[S:3]([C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])(=[O:5])=[O:4].NC(N)=[S:38].[OH-].[Na+].Cl>C(C(C)=O)C.C(Cl)Cl.O>[CH3:1][N:2]([C:19]([F:35])([F:34])[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][SH:38])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)[S:3]([C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])(=[O:5])=[O:4]
Reactant: NC(N)=S
Reactant: CN(C(F)(F)c1ccc(-c2ccc(CCl)cc2)cc1)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCC(C)=O
Product: CN(C(F)(F)c1ccc(-c2ccc(CS)cc2)cc1)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
A mixture of 10.5 g (0.02 mol) of 4-(N-methylperfluorobutanesulfonamidomethyl)-4′-chloromethylbiphenyl, and 1.90 g (0.024 mol) thiourea in 100 mL methyl ethyl ketone was stirred and heated at reflux. The initial solution became cloudy and by 1 hr a white precipitate formed. The mixture was heated for 17 hr, cooled, and filtered. The product (8.2 g) was heated in 150 mL boiling ethanol under N2 and treated with 8 g (0.1 mol) 50% NaOH and heated for 20 hr. The resulting hazy solution was cooled, treated with 20 mL 10% HCl, and poured into 200 mL water to give a white solid. This was taken up in methylene chloride, dried over MgSO4, and stripped to 7.0 g of the desired product.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].O[CH:36]1[CH2:41][CH2:40][CH:39]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:38][CH2:37]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O.C(OCC)(=O)C>[C:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C:6]2[C:5](=[O:27])[N:4]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH:36]4[CH2:41][CH2:40][CH:39]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:38][CH2:37]4)=[CH:30][CH:29]=3)[C:3]([CH2:1][CH3:2])=[N:8][C:7]=2[CH2:9][CH2:10][CH3:11])=[CH:14][CH:15]=1)#[N:26]
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: CCCc1nc(CC)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1nc(CC)n(-c2ccc(OC3CCC(C(=O)OCC)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a solution of 4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.50 g), ethyl 4-hydroxycyclohexanecarboxylate (1.7 g) and triphenylphosphine (2.6 g) in tetrahydrofuran (15 mL) was added diisopropyl azodicarboxylate (5.3 mL, 1.9 M toluene solution), and the mixture was stirred for 1 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.78 g, 88%).
Reaction SMILES: [C:1]12([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:9][CH:8]=3)[CH2:6][CH:5]1[CH2:4][NH:3][CH2:2]2.C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33]>C(Cl)Cl.O>[CH2:35]([O:34][C:32]([N:3]1[CH2:4][CH:5]2[C:1]([C:7]3[CH:8]=[CH:9][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:11][CH:12]=3)([CH2:6]2)[CH2:2]1)=[O:33])[CH:36]=[CH2:37]
Reactant: C=CCOC(=O)Cl
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C34CNCC3C4)cc2)C(=O)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C=CCOC(=O)N1CC2CC2(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2)C1
Yield: 49.2 %

Procedure:
To a solution of hydrochloride salt of N-{3-[4-(3-aza-bicyclo[3.1.0]hex-1-yl)-phenyl]-2-oxo-oxazolidin-5(S)-yl-methyl}-acetamide (Intermediate IV) (100 mg, 0.28 mmol) in dry DCM (5 mL) were added triethylamine (0.16 mL, 1.12 mmol) and allyl chloroformate (0.05 mL, 0.42 mmol) at r.t. and progress of the reaction was monitored by TLC. On completion, the reaction mixture was diluted with water (10 mL) and extracted with DCM (2×20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0.3:9.7 MeOH:CHCl3) to provide the title compound (55 mg, 50%) as white solid.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[CH:7]=1.C(OC([NH:18][C@@H:19]([C@H:28]([C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1)[CH3:29])[C:20]([N:22]1[CH2:26][CH2:25][C@H:24]([F:27])[CH2:23]1)=[O:21])=O)(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.O.C(OCC)(=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[NH2:18][C@@H:19]([C@H:28]([C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[N:9][N:10]=3)[CH:7]=2)=[CH:32][CH:31]=1)[CH3:29])[C:20]([N:22]1[CH2:26][CH2:25][C@H:24]([F:27])[CH2:23]1)=[O:21]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Reactant: Ic1ccc2nncn2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](c1ccc(-c2ccc3nncn3c2)cc1)[C@H](N)C(=O)N1CC[C@H](F)C1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the product (48.0 mg, 0.195 mmol) from Step B in 0.75 mL of ethylene glycol dimethyl ether and 0.75 mL of water was added 62.0 mg (0.13 mmol) of (3S)-1-[(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-oxobutanyl]-3-fluoropyrrolidine from Example 10, Step B, 1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride (21.0 mg, 0.26 mmol) and potassium phosphate (83 mg, 0.39 mmol). The reaction mixture was heated at 90° C. for 16 h, and then allowed to cool to room temperature. The mixture was diluted with ethyl acetate, and the solution was washed sequentially with water and saturated aqueous brine, dried (magnesium sulfate), and concentrated under reduced pressure in vacuo to yield the crude coupled product, which was purified by preparative thin layer chromatography (silica gel, 5% methanol/dichloromethane eluant). The resultant product was dissolved in 1 mL of dichloromethane and was treated with 1 mL of trifluoroacetic acid. The reaction was stirred at room temperature for 1 h, and was then concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (silica gel, 10% methanol/1% ammonium hydroxide/dichloromethane eluant) to afford the title compound. LC/MS 368.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Mg].Br[C:11]1[CH:15]=[CH:14][S:13][CH:12]=1>C1COCC1.C(OCC)C.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ni]Cl>[S:13]1[CH:14]=[CH:15][C:11]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)=[CH:12]1
Reactant: Brc1ccsc1
Reactant: Cc1ccc(Br)cc1
Agent: Cl[Ni]Cl
Agent: [Mg]
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccsc2)cc1
Reaction time: 0.17 h

Procedure:
A solution of 4-bromotoluene (0.9 ml, 7.3 mmol) in THF (3 ml) is added to dried magnesium turnings (0.815 g, 33.5 atoms) under nitrogen atmosphere. After the exothermic reaction initiates, a solution of 4-bromotoluene (3.16 ml, 25.7 mmol) in THF (3 ml) is dropped to the reaction mixture. The stirring is continued for 10 min. The mixture is dropped to a suspension of 3-bromothiophene (2.8 ml, 29.9 mmol) and [1,2-bis(diphenylphosphino)-ethane]nickel(II) chloride (0.72 g, 1.4 mmol) in diethyl ether (50 ml), which has been stirred for 10 min. The reaction mixture is cooled and quenched with 1N hydrochloric acid and extracted with ether. The organic layer is washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate and concentrated in vacuo. The residue is recrystallized from ethanol to give 4-(3-thienyl)toluene.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].Cl[SiH:9]([CH3:11])[CH3:10].C(N(CC)CC)C>CCCCCCC>[CH2:1]([N:4]([SiH:9]([CH3:11])[CH3:10])[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3]
Reactant: C=CCNCC=C
Reactant: C[SiH](C)Cl
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Product: C=CCN(CC=C)[SiH](C)C

Procedure:
The preparation of an azasilacyclobutanes can be illustrated by the following: Diallylamine was reacted with chlorodimethylsilane in heptane in the presence of triethylamine to give diallylaminodimethylsilane as shown by the following equation ##STR24## The silane product was obtained by ambient pressure distillation after removal of triethylamine hydrochloride by filtration. 1-allyl-2,2,3-trimethyl-1-aza-2-silacyclobutane was made by intramolecular hydrosilation of the diallyldimethylsilane. This reaction was carried out at 80° C. in the presence of PtCl2 (PPh3)2 in benzene. The starting material was consumed in four hours to give a product mixture of 83 mole percent of the azasilacyclobutane and 17 mole percent of azasilacyclopentane as illustrated by the following equation ##STR25## Total yield of product was 77 weight percent. The azasilacyclobutane can be reacted with 1,1,3,3-tetramethyldisiloxane in the presence of a platinum catalyst which in turn can be reacted with an alkoxysilane having aliphatic unsaturation as described above to make an azasilacyclobutyl functional alkoxysilane of Formula (A).
Reaction SMILES: [NH2:1][C:2]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][C:5]([CH2:6][C@@H:7]([CH2:11][C:12](=[O:31])[N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[NH:21][C:20]3=[O:30])[CH2:15][CH2:14]2)[C:8](O)=[O:9])=[CH:4][C:3]=1[Cl:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:70][N:71]1[CH2:76][CH2:75][CH:74]([NH:77][S:78]([N:81]2[CH2:86][CH2:85][NH:84][CH2:83][CH2:82]2)(=[O:80])=[O:79])[CH2:73][CH2:72]1>C1COCC1.CCOC(C)=O.CN(C=O)C>[CH3:70][N:71]1[CH2:76][CH2:75][CH:74]([NH:77][S:78]([N:81]2[CH2:86][CH2:85][N:84]([C:8](=[O:9])[C@@H:7]([CH2:6][C:5]3[CH:32]=[C:33]([C:34]([F:36])([F:37])[F:35])[C:2]([NH2:1])=[C:3]([Cl:38])[CH:4]=3)[CH2:11][C:12](=[O:31])[N:13]3[CH2:18][CH2:17][CH:16]([N:19]4[CH2:25][CH2:24][C:23]5[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=5[NH:21][C:20]4=[O:30])[CH2:15][CH2:14]3)[CH2:83][CH2:82]2)(=[O:80])=[O:79])[CH2:73][CH2:72]1
Reactant: Nc1c(Cl)cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Reactant: CN1CCC(NS(=O)(=O)N2CCNCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CCC(NS(=O)(=O)N2CCN(C(=O)[C@H](CC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)Cc3cc(Cl)c(N)c(C(F)(F)F)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 500 mg (0.90 mmol) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butanoic acid and 320 mg (1.00 mmol) TBTU in 0.2 mL (1.14 mmol) ethyldiisopropylamine and 50 mL THF was stirred for 1 h at RT. Then 270 mg (1.03 mmol) piperazin-1-sulphonic acid-(1-methyl-piperidin-4-yl)-amide and 5 mL DMF were added. The reaction solution was stirred overnight at RT. The reaction mixture was diluted with 50 mL EtOAc, extracted with 30 mL 15% K2CO3 solution and the organic phase was dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was purified by chromatography (silica gel, gradient: DCM to DCM/MeOH/NH3 10:9:1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:15]1([CH2:18]Br)[CH2:17][CH2:16]1>CN(C)C=O.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:18][CH:15]2[CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Brc1ccc(SCC2CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.4 %

Procedure:
4-Bromothiophenol (37.8 g) in N,N-dimethylformamide (200 mL) was treated with potassium carbonate (30.4 g) and cyclopropylmethyl bromide (29.7 g). The suspension was stirred at ambient temperature for 16 hrs then diluted with diethyl ether (500 mL). The organic phase was washed with water (2×500 mL), dried (MgSO4) and concentrated to give the title compound as an oil (46.4 g). 1H NMR (360 MHz, CDCl3): δ 7.38 (2H, d, J=8.0 Hz), 7.21 (2H, d, J=8.0 Hz), 2.83 (2H, d, J=7.0 Hz), 1.08-0.98 (1H, m), 0.58 (2H, q, J=5.1 Hz), 0.24 (2H, q, J=5.1 Hz).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C(O)C>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:3][CH2:2][C:1]#[N:4])[CH2:15][CH2:14]1
Reactant: C=CC#N
Reactant: COc1ccccc1N1CCNCC1
Solvent: CCO
Product: COc1ccccc1N1CCN(CCC#N)CC1
Reaction time: 18 h
Yield: 91.7 %

Procedure:
A solution of acrylonitrile (1.06 g, 20 mmol) in ethanol (50 ml) was added to a stirred solution of 2-methoxyphenylpiperazine (3.84 g, 20 mmol) in ethanol (100 ml). After 18 h, the solvent was evaporated in vacuo to give the product (4.5 g) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.[NH2:11][CH:12]1[CH2:17][S:16][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[S:14][CH2:13]1.C(N(CC)CC)C>O.C(Cl)Cl>[Cl:8][C:7]1[C:2]([NH:11][C@H:12]2[CH2:13][S:14][C@@H:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[S:16][CH2:17]2)=[N:3][CH:4]=[N:5][C:6]=1[CH2:9][CH3:10]
Reactant: Cc1ccc(C2SCC(N)CS2)cc1
Reactant: CCc1ncnc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCc1ncnc(N[C@H]2CS[C@@H](c3ccc(C)cc3)SC2)c1Cl

Procedure:
1.77 g (10 mmol) of 4,5-dichloro-6-ethyl-pyrimidine and 2.2 g (10 mmol) of 5-amino-2-(4-methylphenyl)-1,3-dithian were stirred with 2.02 g of triethylamine at 80-90° C. for 6 hours. The mixture was taken up in water/methylene chloride and the organic phase was dried and concentrated. For purification, the residue was chromatographed over silica gel (eluting agent petroleum ether/ethyl acetate 4:1). This gave 1.0 g of colorless solid (27.3% of theory), melting point: 138-139° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH2:13])=[O:12].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br>CC#N>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:7][C:8]1[CH:9]=[C:10]([C:11]([NH2:13])=[O:12])[CH:14]=[CH:15][CH:16]=1
Reactant: BrCCCCCCBr
Reactant: NC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cccc(OCCCCCCBr)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 66.6 %

Procedure:
K2CO3 (1.38 g, 10 mmol, 1 equiv.) was added to a suspension of 3-hydroxybenzamide (1.37 g, 10 mmol, 1 equiv.) in CH3CN (100 ml). The mixture stirred for 10 min at room temperature, before 1,6-dibromo-hexane (9.76 g, 40 mmol, 4 equiv.) was added. The resulting mixture was stirred at 60° C. for 16 h. After this time, the reaction was cooled to room temperature, any undissolved solids were filtered off and the filtrate evaporated under reduced pressure to dryness. The residue was taken-up in EtOAc and water. The organic phase was separated and washed consecutively with K2CO3 solution, water and brine. Dried with MgSO4 and evaporated under reduced pressure to a small volume. The precipitant solid was filtered and washed with EtOAc/pentane, to give the desired compound as a white solid (2.0 g, 67%), mp 115-117° C. HPLC-MS (method 1): m/z 300 [M]+, 302 [M+2H]+, Rt=4.08 min.