Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[CH:3]=1.[Li+].CC([N-]C(C)C)C.[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=[O:39])=[CH:36][CH:35]=1>C1COCC1>[Br:1][C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:38]([C:37]1[CH:40]=[CH:41][C:34]([Cl:33])=[CH:35][CH:36]=1)[OH:39]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(Br)cnc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Br)cnc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 18.4 %

Procedure:
To a solution of 6-bromo-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.6 g, 1.51 mmol) in THF (10 mL) at −78° C. was added LDA (1.8 M in THF, 4.2 mL, 7.56 mmol) dropwise. The reaction was stirred at −78° C. for 30 min then a solution of 4-chlorobenzaldehyde (0.42 g, 3 mmol) in THF (2 mL) was added. The reaction was stirred at −78° C. for 1 h, quenched with aq. NaHCO3 (5 mL) then diluted with EA (50 mL) and water (20 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography PE/EA (4:1) to give 6-bromo-5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (150 mg, 18.5% yield) as a white solid. LCMS: [M+-THP] 436 and TR=1.900 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[CH3:9][C@H:10]1[CH2:15][C:14](=[O:16])[CH2:13][CH2:12][O:11]1>>[OH:16][C@:14]1([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=2)[CH2:13][CH2:12][O:11][C@@H:10]([CH3:9])[CH2:15]1
Reactant: C[C@H]1CC(=O)CCO1
Reactant: Brc1cccc(Br)c1
Product: C[C@H]1C[C@@](O)(c2cccc(Br)c2)CCO1
Yield: 66 %

Procedure:
Using an analogous procedure to that described in the portion of Example 6 which is concerned with the preparation of starting materials, 1,3-dibromobenzene was reacted with (2S)-2-methyltetrahydropyran-4-one to give (2S,4R)-4-hydroxy-4-(3-bromophenyl)-2-methyltetrahydropyran in 66% yield as an oil.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:13][CH2:12][C@H:11]([NH:14]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(O)C=CC=CC=1.Br>C(O)(=O)C>[NH2:14][C@H:11]1[CH2:12][CH2:13][N:9]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:10]1
Reactant: Cc1ccc(S(=O)(=O)N[C@H]2CCN(Cc3ccccc3)C2)cc1
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Solvent: Oc1ccccc1
Product: N[C@H]1CCN(Cc2ccccc2)C1

Procedure:
(S)-1-Benzyl-3-(p-toluenesulfonyl-amino)pyrrolidine hydrochloride (40.0 g), phenol (12.0 g) and 30% hydrogen bromide in acetic acid (200 mL) were combined and heated in a sealed flask at 105° C. to 125° C. for a period of 55 minutes. The resulting red solution was concentrated under vacuum to remove excess acetic acid and hydrogen bromide and the thick oil dissolved in water (500 mL) and toluene (150 mL). The layers were separated and the aqueous layer extracted with toluene (50 mL) and diethyl ether (30 mL) and treated with 28% ammonium hydroxide (11 mL) to give a pH of 8.5. This solution was extracted with toluene (25 mL) and all of the organic extracts discarded. The remaining aqueous layer was treated with 50% NaOH (145 mL) and extracted with toluene (3×50 mL). The combined toluene extracts were concentrated to an oil (19.2 g) which was distilled under vacuum (bp 104°-106° C. at 2.5 mm Hg) to give (S)-3-amino-1-benzylpyrrolidine, 5, (18.2 g, 94%) as a colorless oil: [α]25 =+11.2°.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:21][C:22]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:23]=1[C:24](Cl)=[O:25]>>[F:21][C:22]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:23]=1[C:24]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:25]
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1cc(F)ccc1F
Product: CCOC(=NC(=O)c1cc(F)ccc1F)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 2,5-difluorobenzoyl chloride, there is obtained ethyl N-(2,5-difluorobenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e: M+ 406 (4), 377 (18), 194 (100), 141 (49);
Reaction SMILES: [Cl-].[NH2:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:6]([C:18]#[N:19])=[C:5]([Cl:20])[N+:4]=1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[CH2:29]([N:31]([CH2:35][CH3:36])[C:32](=[S:34])[S-:33])[CH3:30].[Na+]>CN(C)C=O>[Cl-:20].[NH2:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:6]([C:18]#[N:19])=[C:5]([S:34][C:32](=[S:33])[N:31]([CH2:35][CH3:36])[CH2:29][CH3:30])[N+:4]=1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCNc1cc(N)[n+](CCCCCCCC)c(Cl)c1C#N
Reactant: CCN(CC)C(=S)[S-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCNc1cc(N)[n+](CCCCCCCC)c(SC(=S)N(CC)CC)c1C#N
Yield: 29.5 %

Procedure:
4.5 gms (.01 mole) of 2-amino-6-chloro-5-cyano-1-n-octyl-4-n-octylamino pyridinium chloride (compound 14 - Table 1) was dissolved in dimethylformamide and 2.2 gms (0.01 mole) of sodium diethyldithiocarbamate added and the solution refluxed for 60 minutes. This was then cooled, filtered and the solvent evaporated off. Methanol was added and 1.6 gms (30% yield) of 2-amino-5-cyano-6-diethylthiocarbamylthio-1-n-octyl-4-n-octylamino pyridinium chloride (compound 80 - Table 5) was filtered off and recrystallised from methanol (MPt 124° - 126°C.)
Reaction SMILES: [OH:1][CH:2]([CH:4]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=O)[CH3:3].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[NH2:46][CH:47]([C:50]1[C:51](=[O:67])[NH:52][C:53]([CH2:56][C:57]2[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[C:59]([O:65][CH3:66])[CH:58]=2)=[N:54][N:55]=1)[CH2:48][CH3:49]>>[CH3:66][O:65][C:59]1[CH:58]=[C:57]([CH:62]=[CH:61][C:60]=1[O:63][CH3:64])[CH2:56][C:53]1[NH:52][C:51](=[O:67])[C:50]([CH:47]([NH:46][C:5](=[O:7])[CH:4]([CH:2]([OH:1])[CH3:3])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:48][CH3:49])=[N:55][N:54]=1
Reactant: CCC(N)c1nnc(Cc2ccc(OC)c(OC)c2)[nH]c1=O
Reactant: CC(O)C(CCCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCC(NC(=O)C(CCCc1ccccc1)C(C)O)c1nnc(Cc2ccc(OC)c(OC)c2)[nH]c1=O

Procedure:
1.44 g (6.50 mmol) 2-(1-hydroxyethyl)-5-phenylpentanoic acid are reacted analogously to Example 39A with 1.00 g (6.50 mmol) of 1-hydroxy-1H-benzotriazole, 1.97 g (19.5 mmol) of 4-methylmorpholine, 1.25 g (6.350 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 2.15 g (6.32 mmol) of 6-(1-aminopropyl)-3-(3,4-dimethoxybenzyl)-1,2,4-triazin-5(4H)-one to give N-{1-[3-(3,4-dimethoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}-2-(1-hydroxyethyl)-5-phenylpentanamide.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[CH:5][C:4]=1[CH:14]([OH:16])[CH3:15])[CH3:2]>C1COCC1.O=[Mn]=O>[CH2:1]([C:3]1[N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:6]=[CH:5][C:4]=1[C:14](=[O:16])[CH3:15])[CH3:2]
Reactant: CCc1c(C(C)O)cnn1-c1ccccc1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: CCc1c(C(C)=O)cnn1-c1ccccc1
Yield: 98.6 %

Procedure:
A solution of 7.9 g (36.5 mmol) of 1-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-ethanol in 100 mL THF was stirred at rt over 24 g of activated MnO2 for 23 h. The mixture was filtered through Celite and concentrated to give 1-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-ethanone (7.71 g). ESI MS m/z 215 [C13H14N2O+H]+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[N:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH:9]=1)=[N+]=[N-].O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1>[CH3:19][S:16]([C:13]1[CH:12]=[CH:11][C:10]([N:8]2[CH:9]=[C:5]([CH2:4][NH2:1])[CH:6]=[N:7]2)=[CH:15][CH:14]=1)(=[O:17])=[O:18]
Reactant: CS(=O)(=O)c1ccc(-n2cc(CN=[N+]=[N-])cn2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-n2cc(CN)cn2)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-azidomethyl-1-(4-methanesulfonyl-phenyl)-1H-pyrazole (1.90 g, 7.12 mmol, 1.00 equiv) in 1,4-dioxane (10 mL) was added water (1 mL) and triphenylphosphine resin (2.8 g, 3 mol/g, 200-400 mesh, 1.2 equiv). The suspension was stirred overnight. Filtration and concentration afforded C-[1-(4-methanesulfonyl-phenyl)-1H-pyrazol-4-yl]-methylamine as a colorless solid. LCMS: (MH)+=252.1 (0.55 min). This compound was utilized in the following Example 22.1.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[CH2:7]([NH:9][CH2:10][CH3:11])[CH3:8]>C1COCC1>[Br:1][CH2:2][CH2:3][C:4]([N:9]([CH2:10][CH3:11])[CH2:7][CH3:8])=[O:5]
Reactant: O=C(Cl)CCBr
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)CCBr
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-bromopropanoyl chloride (1.0 g, 5.8 mmol) and diethylamine (1.9 g, 26 mmol) in THF (20 ml) was stirred at 0° C. for 30 min, the resulting white solid was filtered and the filtrate was concentrated to give a crude oil which was used in the next reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@:12]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:18][CH:17]=2)([CH3:13])[CH2:11]OS1(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:32]#[N:33].[Na+].CCOC(C)=O.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@:12]([CH2:11][C:32]#[N:33])([CH3:13])[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:20][CH:21]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CCCCCCCOc1ccc(CC[C@]2(C)COS(=O)(=O)N2C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCOc1ccc(CC[C@](C)(CC#N)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 25 h

Procedure:
To a stirred solution of (R)-4-[2-(4-heptyloxy-phenyl)-ethyl]-4-methyl-2,2-dioxo-2λ*6*-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (174 mg, 0.40 mMol) in DMF (5 ml) is added sodium cyanide (94 mg, 1.91 mMol). The mixture is stirred at RT for 25 hours. Additional sodium cyanide (37 mg, 0.76 mMol) is added and the mixture is stirred at RT for 18 hours. The reaction mixture is then poured onto a biphasic mixture of AcOEt and NaHCO3 (saturated aqueous solution). The aqueous phase is extracted twice with AcOEt. The combined organic layers are dried (Na2SO4) and concentrated under reduced pressure. Column chromatography eluting with 5% AcOEt in toluene gives the title compound as a colourless oil.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[CH3:17].[F:18][C:19]([F:33])([F:32])[O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[O:28])=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH3:17])=[C:2]([C:26]3[CH:25]=[C:24]([CH:23]=[CH:22][C:21]=3[O:20][C:19]([F:18])([F:32])[F:33])[CH:27]=[O:28])[CH:11]=2)[C:6]([CH3:16])([CH3:15])[CH2:7][C:8]1=[O:14])[CH3:13]
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(Br)cc21
Reactant: O=Cc1ccc(OC(F)(F)F)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C=O)ccc3OC(F)(F)F)cc21
Yield: 64.9 %

Procedure:
A solution of Compound 1A (1 g, 3.38 mmol) in 17 mL of toluene was added to a flask containing 2-trifluoromethoxy-5-formyl-phenyl boronic acid (0.95 g, 4.05 mmol), prepared by the procedure described in WO 03/075924, and tetrakis(triphenylphosphine)palladium(0) (195 mg, 0.17 mmol) in 4 mL of toluene. Next, 3.4 mL of a 2M solution of potassium carbonate was added and the reaction heated to reflux for four hours, after which the reaction was cooled and partitioned between ethyl acetate (100 mL) and water (50 mL). The aqueous layer was further extracted with ethyl acetate (2×100 mL) and the combined organic layers were dried with sodium sulfate, filtered, stripped and purified via flash chromatography (15% EtOAc/hexanes) to afford 890 mg of product Compound 2A (65%). MS (electrospray): mass calculated for C22H22F3NO3, 405.16; m/z found 406.2, [M+H]+.
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][NH:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[CH3:14][C:15]([CH3:20])([CH3:19])[C:16](Cl)=[O:17].C(N(CC)CC)C>C(Cl)Cl>[CH3:14][C:15]([CH3:20])([CH3:19])[C:16]([N:2]1[CH2:3][CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:1]1)=[O:17]
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)N1CCc2c([nH]c3ccccc23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
To a solution of 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (2 g, 11.6 mmol) dissolved in methylene chloride (20 mL) is added 2,2-dimethyl-propionyl chloride (1.42 mL, 11.6 mmol) followed by the addition of triethylamine (1.61 mL, 11.6 mmol). The reaction mixture is stirred at room temperature for 30 minutes The reaction is quenched with water and extracted with methylene chloride three times. The combined organic extracts are washed with saturated sodium bicarbonate, a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo to give 2.8 g (94%) of the title compound as a grey solid.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[C:13](C(OCC)=O)[C:12]2=[O:29])=[CH:2]1>CN(C)C=O>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[C:12](=[O:29])[CH:13]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[O:15]2)=[CH:2]1
Reactant: CCOC(=O)C1=C(Nc2ccccc2Cl)OC(=Cc2c[nH]c3ncccc23)C1=O
Solvent: CN(C)C=O
Product: O=C1C=C(Nc2ccccc2Cl)OC1=Cc1c[nH]c2ncccc12
Temperature: 25 °C
Yield: 12.3 %

Procedure:
A solution of the compound (0.050 g, 0.12 mmol) of Example 15 in N,N-dimethylformamide (1.0 mL) was stirred at 150° C. for 6 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.0050 g, y. 11%).
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([Cl:9])[C:6]([Cl:10])=[CH:5][CH:4]=1.[C-:11]#[N:12].[Na+]>O>[Cl:10][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][C:11]#[N:12])=[N:8][C:7]=1[Cl:9]
Reactant: [C-]#N
Reactant: Clc1ccc(CBr)nc1Cl
Agent: [Na+]
Solvent: O
Product: N#CCc1ccc(Cl)c(Cl)n1
Temperature: 100 °C
Yield: 58.3 %

Procedure:
To a solution of 6-(bromomethyl)-2,3-dichloropyridine (Preparation 60, 2.90 g, 3.13 mmol) in IMS (20 mL) and water (15 mL) was added NaCN (552 mg, 11.3 mmol). The reaction was heated to 100° C. for 1 hour before cooling to room temperature and quenching with saturated aqueous NaHCO3 solution (50 mL). The mixture was extracted with DCM (3×50 mL) and the organic layers combined, dried over MgSO4 and concentrated in vacuo. The residue was purified using reverse phase column chromatography eluting with 0-100% MeCN in water with 0.1% formic acid to afford the title compound (341 mg, 15% over two steps).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH2:12][CH2:11][CH2:10]2.CC(C)([O-])C.[K+]>C1COCC1.C(OCC)(=O)C>[CH2:3]([CH:12]1[CH2:11][CH2:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([O:6][CH3:5])[CH:8]=2)[C:13]1=[O:17])[CH:2]=[CH2:1]
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: C=CCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCC1CCc2cc(OC)ccc2C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.5 %

Procedure:
Allyl bromide (5.4 g, 45.0 mmol) was added to a solution of 6-methoxy-1-tetralone (10.0 g, 56.0 mmol) and potassium tert-butoxide in THF (50 mL), and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then diluted with ethyl acetate. The separated organic layer was washed with water, brine solution, dried over sodium sulphate, filtered and removed under reduced pressure. The product was purified by flash chromatography using 4% ethyl acetate in hexanes to afford title compound (2.0 g, 15%) as solid. 1H NMR (400 MHz, CDCl3): δ 8.01 (d, J=8.4 Hz, 1H), 6.80 (dd, J1=2.8 Hz, J2=8.8 Hz, 1H), 6.68 (m, 1H), 5.89-5.79 (m, 1H), 5.12 (t, J=17.2 Hz, 2H) 3.85 (s, 3H), 2.95 (m, 2H), 2.93-2.72 (m, 1H), 2.53-2.46 (m, 1H), 2.29-2.17 (m, 2H), 1.89-1.79 (m, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:14]=[C:13]([C:15](=[O:42])[CH2:16][C@H:17]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]3)=[CH:27][CH:26]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[CH:12]=[CH:11][N:10]=1>ClCCl>[NH:33]1[CH2:34][CH:31]([C:28]2[CH:29]=[CH:30][C:25]([C@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[CH2:16][C:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([CH3:8])[CH:14]=3)=[O:42])=[CH:26][CH:27]=2)[CH2:32]1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C3CN(C(=O)OC(C)(C)C)C3)cc2)c2ccccc2C)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)C[C@H](c2ccc(C3CNC3)cc2)c2ccccc2C)ccn1
Yield: 115.9 %

Procedure:
Trifluoroacetic acid (1.37 g, 927 μl, 12.0 mmol) was added at 0° C. to a solution of (R)-tert-butyl 3-(4-(3-(2-methylpyridin-4-yl)-3-oxo-1-o-tolylpropyl)phenyl)azetidine-1-carboxylate (283 mg, 601 μmol, Eq: 1.00) in dichloromethane (2 mL). The ice bath was removed, then after 2 h the reaction mixture was partitioned between sat. aq. sodium hydrogencarbonate solution and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated to afford the title compound (258 mg, purity ca. 85%), which was used for the next step without purification. Off-white foam, MS (ESI+): m/z=371.0 ([M+H]+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][CH2:20][CH2:21][N:22]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])[CH2:14]1.[CH3:33][C:34]([O:37][C:38]([NH:40][C@@H:41]([C:51](O)=[O:52])[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:44]=1[Cl:50])=[O:39])([CH3:36])[CH3:35]>C1C=NC2N(O)N=NC=2C=1.CN(C=O)C>[C:34]([O:37][C:38](=[O:39])[NH:40][CH:41]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:44]=1[Cl:50])[C:51]([N:16]1[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:14][CH:15]1[CH2:19][CH2:20][CH2:21][N:22]1[C:30](=[O:31])[C:29]2=[CH:28][CH:27]=[CH:26][CH:25]=[C:24]2[C:23]1=[O:32])=[O:52])([CH3:36])([CH3:33])[CH3:35]
Reactant: O=C1c2ccccc2C(=O)N1CCCC1CN(CCc2ccc3ccccc3c2)CCN1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1Cl)C(=O)O
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1Cl)C(=O)N1CCN(CCc2ccc3ccccc3c2)CC1CCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 6-6 (42 mg, 0.10 mmol) and BOC-D-2,4-dichlorophenylalanine (66 mg, 2 eq) in 0.4 mL of 0.5 M HOAt in DMF and 0.5 mL of anhydrous DMF was added diisopropylcarboimide (24 mg, 2 equivalents). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo and the crude was purified with column chromatography (eluted with hexanes, ethyl acetate 1:2). The purified product, {1-(2,4-Dichloro-benzyl)-2-[2-[3-phthalimido-propyl]-4-(2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (6-7) was obtained as white solid, 30 mg (40%).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:14][C:15]([CH3:19])=[N:16]2)=[CH:11][C:10]=1[F:25])C1C=CC=CC=1>CO.[Pd]>[F:25][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[OH:8])[N:16]=[C:15]([CH3:19])[CH:14]=[C:13]2[N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1cc(N2CCCC2)c2cc(F)c(OCc3ccccc3)cc2n1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N2CCCC2)c2cc(F)c(O)cc2n1
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
A solution of 1.5 g (4.46 mmol) of 7-benzyloxy-6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinoline, product of example 99, dissolved in 40 ml of MeOH was treated with 0.375 g of palladium on charcoal (10%) and then hydrogenated at RT for 1.5 h until HPLC analysis indicated the completion of the reaction. The catalyst was filtered off, and the solution was concentrated in vacuo. The residue was triturated with AcOEt, collected by filtration and dried in a high vacuum to give 1.02 g (92.8%) 6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol as an yellow solid. ISP mass spectrum, m/e: 247.3 (M+1 calculated for C14H15FN2O: 247).
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 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 ##STR13## 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 ##STR14## 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: [CH2:1]([C:3](=[CH:18][CH3:19])[CH:4]=[CH:5][CH2:6][N:7]1C(=O)C2=CC=CC=C2C1=O)[CH3:2].O.NN.C(O)C>[OH-].[Na+]>[CH2:18]([C:3](=[CH:1][CH3:2])[CH:4]=[CH:5][CH2:6][NH2:7])[CH3:19]
Reactant: CC=C(C=CCN1C(=O)c2ccccc2C1=O)CC
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC=C(C=CCN)CC

Procedure:
A mixture of N-(4-ethyl-2,4-hexadien-1-yl)phthalimide (3.0 g), hydrazine monohydrate (0.88 g), and ethanol (30 ml) was refluxed for 40 minutes under nitrogen atmosphere. After cooling, the precipitate was filtered and washed with ethanol. Evaporation of the filtrate gave a crystalline residue which was dissolved in 1N sodium hydroxide solution and extracted with dichloromethane. The organic extract was washed with water and brine, dried over anhydrous sodium sulfate, and evaporated to give 4-ethyl-2,4-hexadien-1-ylamine as an oil. To a mixture of crude 4-ethyl-2,4-hexadien-1-ylamine, triethylamine 1.79 g), and dichloromethane (30 ml) at 0° C. was added dropwise dimethylsulfamoyl chloride (2.03 g) during 10 minutes. After 30 minutes, triethylamine (0.6 g) and dimethylsulfamoyl chloride (0.85 g) were added to the reaction mixture. After 1 hour at 0° C., the reaction mixture was washed with water and aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (dichloromethane-hexane, 7:3) to give N,N-dimethyl-N'-(4-ethyl-2,4-hexadien-1-yl)-sulfamide (924 mg) as an oil.