Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([OH:14])=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:34][N:35]1[CH2:40][CH:39]=[C:38]([CH2:41]O)[CH2:37][CH2:36]1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:14][CH2:41][C:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH:37]=3)=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CN1CC=C(CO)CC1
Reactant: CC(=O)N1CCc2cc(O)c(Br)cc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)N1CCc2cc(OCC3=CCN(C)CC3)c(Br)cc21
Temperature: 32 °C
Yield: 73.6 %

Procedure:
A stirred suspension of powdered 1-acetyl-6-bromo-2,3-dihydro-1H-indol-5-ol (Tetrahedron, 1973, 29(8), 1115) (19 g, 0.074 mole) in dry THF (1700 ml) at room temp. under argon was treated with triphenylphosphine (19.6 g, 0.075 mole) and 1-methyl-1,2,3,6-tetrahydropyridine-4-methanol (J. Med. Chem., 1988, 31, 545) (9.5 g, 0.075 mole), followed by the dropwise addition over 15 mins. of a solution of diethyl azodicarboxylate (11.8 ml, 0.075 mole) in THF (40 ml). A mild exotherm occured and the insoluble material dissolved. The solution was warmed at 32° C. for 1 hour, then concentrated in vacuo to approx. 500 ml volume. The solid which had formed was filtered off and dried according 16.1 g of beige solid. The filtrate was concentrated in vacuo and the residue treated with ethyl acetate (700 ml) and 1M HCl acid (500 ml), shaken well and the acid layer separated. This was washed with ethyl acetate, then basified with 40% NaOH and extracted with ethyl acetate, followed by chloroform. The combined extracts were dried (Na2SO4) and concentrated in vacuo to leave a yellow solid, which was recrystallised from ethyl acetate (3.8 g) giving a total yield of 19.9 g (74%) of 1-acetyl-6-bromo-2,3-dihydro-5-(1-methyl-1,2,3,6-tetrahydropyridin-4-ylmethoxy)-1H-indole.
Reaction SMILES: CN(CCO)C.[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[C:15]1[C:16]([Cl:23])=[N:17][C:18]([Cl:22])=[CH:19][C:20]=1[Cl:21].C([Li])CCC.[Br:29]C(F)(F)C(F)(F)Br.Cl>O1CCCC1>[Br:29][C:19]1[C:20]([Cl:21])=[C:15]([C:9]2[C:10]([F:14])=[CH:11][CH:12]=[CH:13][C:8]=2[Cl:7])[C:16]([Cl:23])=[N:17][C:18]=1[Cl:22]
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: Fc1cccc(Cl)c1-c1c(Cl)cc(Cl)nc1Cl
Agent: CN(C)CCO
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Fc1cccc(Cl)c1-c1c(Cl)nc(Cl)c(Br)c1Cl
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
At room temperature, 2.0 g (22.4 mmol) of N,N-dimethylaminoethanol were added to 2.0 g (6.4 mmol) of 3-(2-chloro-6-fluorophenyl)-2,4,6-trichloropyridine (see Example Ab) dissolved in 25 ml of tetrahydrofuran, and the mixture was cooled to −78° C. 26 ml (41.9 mmol) of n-butyllithium (1.6 M in hexane) were then added dropwise, and the mixture was stirred at −75° C. to −50° C. for 1.5 h. 4.0 g (15.4 mmol) of 1,2-dibromotetra-fluoroethane were then added dropwise, and the mixture was stirred at −50° C. to −70° C. for 1 h, thawed to room temperature, added to 70 ml of 10% strength hydrochloric acid, extracted three times with in each case 80 ml of methyl tert-butyl ether, dried over sodium sulfate, concentrated under reduced pressure and triturated with hexane. Yield 1.6 g. 1H-NMR (CDCl3) δ=7.15 (m); 7.40 (m).
Reaction SMILES: C([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:18])=[C:16]([Cl:17])[N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([O:19][CH2:20][CH2:21][O:22][CH3:23])[C@H:6]([O:24]C(=O)C(C)(C)C)[C@H:5]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=O)C.[OH-].[K+].O.NN>CO>[Cl:17][C:16]1[N:11]2[CH:10]=[CH:9][C:8]3[C@@H:7]([O:19][CH2:20][CH2:21][O:22][CH3:23])[C@H:6]([OH:24])[C@@H:5]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[NH:4][C:13]=3[C:12]2=[N:14][C:15]=1[CH3:18]
Reactant: COCCO[C@@H]1c2ccn3c(Cl)c(C)nc3c2N(C(C)=O)[C@H](c2ccccc2)[C@H]1OC(=O)C(C)(C)C
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCO[C@@H]1c2ccn3c(Cl)c(C)nc3c2N[C@H](c2ccccc2)[C@H]1O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A suspension of 0.27 g (0.53 mmol) (7R,8R,9R)-10-acetyl-3-chloro-7-(2-methoxyethoxy)-2-methyl-9-phenyl-8-pivaloyloxy-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine, 0.10 ml (0.60 mmol) aqueous potassium hydroxide (6 N) and 0.20 ml (5.14 mmol) hydrazine hydrate in methanol is stirred at 60° C. for 4 h. The methanol is removed in vacuo and the reaction mixture is diluted with water. Subsequently the mixture is extracted twice with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is purified by column chromatography (toluene/dioxane/acetic acid: 8/1/1) to provide 0.34 g (0.88 mmol/51%) of the title compound as a colourless solid with a melting point of 123-126° C. (acetone).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([CH2:13][C@@H:14]([OH:17])[CH2:15][CH3:16])[N:11]=[C:10]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)[N:9]=2)[CH:5]=[C:4]([CH3:27])[N:3]=1.[CH3:28][CH2:29]N(CC)CC.S1C=CC=C1>C1COCC1.[Pd]>[F:26][C:21]1[CH:20]=[C:19]([NH:18][C:10]2[N:9]=[C:8]([C:6]3[CH:7]=[CH:2][N:3]=[C:4]([CH3:27])[CH:5]=3)[N:12]([CH2:13][CH:14]([OH:17])[CH2:15][CH2:16][CH2:28][CH3:29])[N:11]=2)[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: CCN(CC)CC
Reactant: CC[C@H](O)Cn1nc(Nc2ccc(F)c(F)c2)nc1-c1cc(C)nc(Cl)c1
Agent: [Pd]
Solvent: c1ccsc1
Solvent: C1CCOC1
Product: CCCCC(O)Cn1nc(Nc2ccc(F)c(F)c2)nc1-c1ccnc(C)c1

Procedure:
A mixture of intermediate, 1-[5-(2-chloro-6-methyl-pyridin-4-yl)-3-(3,4-difluoro-phenylamino)-[1,2,4]triazol-1-yl]-hexan-2-ol (prepared according to D4) (1.5 g; 3.5 mmol) and Et3N (2 ml) in THF (40 ml) was hydrogenated with Pd/C 10% (0.020 g) as a catalyst in the presence of thiophene solution (0.1 ml; 4% in DIPE). After uptake of H2 (1 equiv) had ceased, the catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was suspended in DIPE and filtrated. The crystals were dried in a vacuum oven at 70° C. overnight.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[S:10]([CH2:13][CH:14]([CH3:16])[CH3:15])(=[O:12])=[O:11])[CH2:3][CH2:2]1.[CH3:20][C:21]1([CH3:26])[CH2:25][CH2:24][CH2:23][NH:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([N:22]3[CH2:23][CH2:24][CH2:25][C:21]3([CH3:26])[CH3:20])=[O:19])=[N:8][C:9]=2[S:10]([CH2:13][CH:14]([CH3:15])[CH3:16])(=[O:11])=[O:12])[CH2:2][CH2:3]1
Reactant: CC(C)CS(=O)(=O)c1nc(C(=O)O)ccc1C1CC1
Reactant: CC1(C)CCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CS(=O)(=O)c1nc(C(=O)N2CCCC2(C)C)ccc1C1CC1

Procedure:
In analogy to the procedure described in Example 47 b), 5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid (Example 6 d)) was reacted with 2,2-dimethylpyrrolidine (CAN 35018-15-6) in the presence of TBTU and DIEA to obtain the title compound as colorless solid; MS (EI): m/e=365.5 [MH+].
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([O:9][C:10]2[C:11]([C:23]([NH2:25])=[O:24])=[N:12][CH:13]=[C:14]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.N1C=CN=C1.[C:31]([Si:35](Cl)([CH3:37])[CH3:36])([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl>[Si:35]([O:1][CH2:2][C:3]1[C:8]([O:9][C:10]2[C:11]([C:23]([NH2:25])=[O:24])=[N:12][CH:13]=[C:14]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NC(=O)c1ncc(Sc2ccccn2)cc1Oc1cccnc1CO
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1ncccc1Oc1cc(Sc2ccccn2)cnc1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
3-(2-(Hydroxymethyl)pyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinamide (575 mg, 1.62 mmol) was dissolved in CH2Cl2 (20 mL) and 1H-imidazole (166 mg, 2.43 mmol) and tert-butylchlorodimethylsilane (293 mg, 1.95 mmol) were added. The reaction was stirred at ambient temperature for 2 hours. The solids were filtered and the filtrate was concentrated. The residue was purified on silica gel (5% methanol in EtOAc) to afford 3-(2-((tert-butyldimethylsilyloxy)methyl)pyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinamide (391 mg, 0.834 mmol, 51.4% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[CH:16]3[C:25]4[C:24](=[O:26])[CH2:23][C:22]([CH3:28])([CH3:27])[CH2:21][C:20]=4[NH:19][C:18]4[NH:29][N:30]=[C:31]([C:32]([O:34]C(C)(C)C)=[O:33])[C:17]3=4)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[CH:16]3[C:25]4[C:24](=[O:26])[CH2:23][C:22]([CH3:27])([CH3:28])[CH2:21][C:20]=4[NH:19][C:18]4[NH:29][N:30]=[C:31]([C:32]([OH:34])=[O:33])[C:17]3=4)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(=O)C2=C(C1)Nc1[nH]nc(C(=O)OC(C)(C)C)c1C2/C=C/c1ccc(-c2cccc(F)c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC(=O)C2=C(C1)Nc1[nH]nc(C(=O)O)c1C2/C=C/c1ccc(-c2cccc(F)c2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
83 mg of tert-butyl 4-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-7,7-dimethyl-5-oxo-4,5,6,7,8,9-hexahydro-1H-pyrazolo[3,4-b]quinoline-3-carboxylate are dissolved in DCM (2.5 ml), admixed with TFA (2.5 ml) and stirred at RT for 3 h. The solvent is removed under reduced pressure, and the residue is suspended in toluene and concentrated by rotary evaporation once again. The resulting solid is used further without purification.
Reaction SMILES: C1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)C=CC=CC=1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:31][CH3:32])=[C:26](B(O)O)[CH:27]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:31][CH3:32])=[C:26]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:27]=1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: COc1ccc(Cl)cc1B(O)O
Product: COc1ccc(Cl)cc1-c1[nH]c2cccc3c2c1CCNC3=O

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (129 mg, 0.49 mmol) and 5-chloro-2-methoxy-phenylboronic acid (100 mg, 0.54 mmol) were coupled to yield 2-(5-chloro-2-methoxy-phenyl)-3,4,5,6-tetrahydro-azepino[5,4,3-cd]indol-6-one, 100 mg (63%) as an off-white solid: m.p. 160-162° C.; 1H NMR (300 MHz, d6-DMSO) δ 2.81 (m, 2H), 3.34 (m, 2H), 3.84 (s, 3H), 7.20 (m, 2H), 7.46 (m, 2H), 7.55 (d, J=7.8 Hz, 1H), 7.68 (d, J=7.5 Hz, 1H), 8.05 (br t, 1H), 11.37 (br s, 1H). MS (FAB, MH+): 327. Anal. (C18H15ClN2O2) C, H, N, Cl.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:23](=[O:40])[CH2:24][CH2:25][C:26]([C:28]2[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=2)=[O:27])[CH:8]=[C:9]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]=1[O:11][CH2:12][CH2:13][CH3:14])(=[O:4])=[O:3].CS(C1C=C([C@@H](O)CCC(C2C=C(OC)C(OC)=C(OC)C=2)=O)C=C(OCC2C=CC=CC=2)C=1OCCC)(=O)=O>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:23]([OH:40])[CH2:24][CH2:25][CH:26]([C:28]2[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=2)[OH:27])[CH:8]=[C:9]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]=1[O:11][CH2:12][CH2:13][CH3:14])(=[O:3])=[O:4]
Reactant: CCCOc1c(OCc2ccccc2)cc(C(=O)CCC(=O)c2cc(OC)c(OC)c(OC)c2)cc1S(C)(=O)=O
Agent: CCCOc1c(OCc2ccccc2)cc([C@@H](O)CCC(=O)c2cc(OC)c(OC)c(OC)c2)cc1S(C)(=O)=O
Product: CCCOc1c(OCc2ccccc2)cc(C(O)CCC(O)c2cc(OC)c(OC)c(OC)c2)cc1S(C)(=O)=O

Procedure:
This compound was prepared from 1-(3-methylsulfonyl-4-n-propoxy-5-benzyloxyphenyl)-4-(3,4,5-trimethoxy- phenyl)butan-1,4-dione as shown for (-)-(1S)-1-(3-methylsulfonyl-4-n-propoxy-5-benzyloxy phenyl)-4-(3,4,5-trimethoxyphenyl) butan-1-ol-4-one and used without further purification.
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: CC(O)C(CCCc1ccccc1)C(=O)O
Reactant: CCC(N)c1nnc(Cc2ccc(OC)c(OC)c2)[nH]c1=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: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[N:16]=[CH:15][C:14]([CH2:17][C:18]#N)=[CH:13][CH:12]=1>>[C:2]1([CH3:1])[CH:8]=[CH:7][C:5]([NH:6][CH2:18][CH2:17][C:14]2[CH:15]=[N:16][C:11]([C:10]([F:21])([F:9])[F:20])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Reactant: Cc1ccc(N)cc1
Product: Cc1ccc(NCCc2ccc(C(F)(F)F)nc2)cc1
Yield: 50.3 %

Procedure:
In analogy to example 9, step 1, 4-methylaniline (298 mg, 2.78 mmol) was coupled to (6-trifluoromethyl-pyridin-3-yl)-acetonitrile (750 mg, 4.03 mmol) to provide the title compound as a pale yellow oil (392 mg, 35%) MS m/e: 281.1 [M+H]+.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[CH:14]([CH3:25])[CH2:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[S:21]([NH2:24])(=[O:23])=[O:22]>C1COCC1>[CH3:25][CH:14]1[CH2:15][C:16]2[CH:20]=[CH:19][S:18][C:17]=2[S:21](=[O:23])(=[O:22])[NH:24]1
Reactant: CC(O)Cc1ccsc1S(N)(=O)=O
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: CC1Cc2ccsc2S(=O)(=O)N1
Temperature: 0 °C
Reaction time: 3 h
Yield: 56.9 %

Procedure:
Triphenylphosphene (3.6 g, 13.76 mmol) and diethyl azodicarboxylate (2.2 mL, 13.76 mmol) were dissolved in THF (10 mL) and cooled to 0° C. To this was added a solution of the product from Step A (1.9 g, 8.6 mmol) in THF (10 mL) and the mixture was stirred at 0° C. for 3 hr. The solvent was evaporated and the residue dissolved in ethyl acetate (100 mL); this solution was washed with water (2×50 mL) and brine (2×50 mL), dried (MgSO4), and evaporated to a syrup which was purified by column chromatography (silica, 1:2 hexane/ethyl acetate) to give the desired product (995 mg, 57%).
Reaction SMILES: [CH2:1]([O:3][C:4]1([O:20][CH2:21][CH3:22])[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[C@H:6]([CH2:18]O)[CH2:5]1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42]1(=[O:52])[NH:46][C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:21]([O:20][C:4]1([O:3][CH2:1][CH3:2])[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])[C@H:6]([CH2:18][N:46]2[C:42](=[O:52])[C:43]3=[CH:51][CH:50]=[CH:49][CH:48]=[C:44]3[C:45]2=[O:47])[CH2:5]1)[CH3:22]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOC1(OCC)CCN([C@@H](C)c2ccccc2)[C@H](CO)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC1(OCC)CCN([C@@H](C)c2ccccc2)[C@H](CN2C(=O)c3ccccc3C2=O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
A suspension of 4,4-diethoxy-1-(1-(S)-phenyl-ethyl)-(S)-2-hydroxymethyl-piperidine (20 g, 65 mmol), triphenylphosphine (18.76 g, 72 mmol) and phthalimide (10.52 g, 72 mmol) in tetrahydrofurane (200 ml) cooled to 0° C. was added diethyl azodicarboxylate (11.34 ml, 72 mmol) over the course of 1 hour. The reaction mixture was stirred at 0° C. for another 2 hours before the volatiles were removed in vacuo. The residue was dissolve in hot heptane-toluene (3:2) (100 ml) before it was cooled on an ice bath. The precipitate was filtered off and washed with heptane. The filtrate was concentrated in vacuo and the residue subjected to column chromatography using a mixture of toluene/ethyl acetate/heptane (3:1:3) as eluent. The solvent was evaporated in vacuo and the residue was crystallized by addition of light petrol ether (250 ml). The precipitate was filtered off, which afforded 24 g (85%) of 4,4-diethoxy-1-(1-(S)-phenyl-ethyl)-2-(S)-phthalimidomethyl-piperidine as a solid.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5](=[O:27])[CH:6]([NH:15][C:16]([CH3:26])=[CH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Br:28][CH2:29][CH2:30]Br>C(O)C>[CH3:3][O:4][C:5](=[O:27])[CH:6]([NH:15][C:16]([CH3:26])=[CH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:30][CH2:29][Br:28])=[CH:12][CH:13]=1
Reactant: BrCCBr
Reactant: COC(=O)C(Cc1ccc(O)cc1)NC(C)=CC(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C(Cc1ccc(OCCBr)cc1)NC(C)=CC(=O)c1ccccc1
Yield: 16.7 %

Procedure:
To a solution of potassium hydroxide (0.17 g, 2.95 mmol) in ethanol (20 ml) is added 2-(1-methyl-3-oxo-3-phenyl-propenylamino)-3-(4-hydroxyphenyl)-propionic acid methyl ester (1.00 g, 2.95 mmol) and 1,2-dibromoethane (5.54 g, 29.50 mmol). Then the mixture is heated to reflux for 8 hours. After cooled, the reaction mixture is filtered to remove the solid formed, and then the filtrate is evaporated under a vacuum. The crude product is purified by silica gel chromatography using hexane/EtOAc (4:1) as eluent to give the title compound (0.22 g, 17%).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11](=[O:14])[C:12]=1I)=[CH:9][C:8]([F:15])=[CH:7][CH:6]=2)[CH3:2].[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[C:21]([F:23])[CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.O.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>[F:16][C:17]1[CH:18]=[C:19]([C:12]2[C:11](=[O:14])[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([F:15])[CH:9]=3)[NH:4][C:3]=2[CH2:1][CH3:2])[CH:20]=[C:21]([F:23])[CH:22]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CCc1[nH]c2ccc(F)cc2c(=O)c1I
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: [Na+]
Solvent: O
Solvent: CC#N
Product: CCc1[nH]c2ccc(F)cc2c(=O)c1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred mixture of 2-ethyl-6-fluoroquinolin-4(1H)-one (4.00 g, 21 mmol), I2 (10.62 g, 2.0 eq) and Na2CO3 (3.33 g, 1.5 eq) in THF (100 mL) was stirred at rt overnight. To the reaction mixture was added Na2S2O3 solution, after 2 min the resulted mixture was filtered, washed with water and dried in the air to give a white solid as 2-ethyl-6-fluoro-3-iodoquinolin-4(1H)-one. Mass Spectrum (ESI) m/e=318 (M+1). A mixture of 2-ethyl-6-fluoro-3-iodoquinolin-4(1H)-one (400 mg, 1.3 mmol), 3,5-difluorophenylboronic acid (398 mg, 2.0 eq), Na2CO3 (401 mg, 3.0 eq) and tetrakis(triphenylphosphine)palladium(0) (73 mg, 0.05 eq) in acetonitrile/water (15 mL/5 mL) was purged with N2 and heated to reflux. After overnight, the reaction mixture was cooled at rt, partitioned between water and EtOAc. The layers were separated and the aq layer was extracted with EtOAc (10 mL×2). The combined organic layers were washed with water (10 mL×2), brine (10 mL), dried over Na2SO4, filtered, and concd under reduced pressure. The residue was purified by combiflash on silica gel (EtOAc/DCM, 1:2) to give 3-(3,5-difluorophenyl)-2-ethyl-6-fluoroquinolin-4(1H)-one as a white solid. Mass Spectrum (ESI) m/e=304 (M+1).
Reaction SMILES: [CH3:1][S:2]([N:5]([C:13]1[CH:14]=[C:15]([O:27][CH2:28][CH:29]2[O:31][CH2:30]2)[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)C(OC(C)(C)C)=O)(=[O:4])=[O:3].[NH2:32][CH:33]1[CH2:42][CH2:41][C:40]2[C:35](=[CH:36][C:37]([O:43][CH2:44][C:45]([N:47]3[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]3)=[O:46])=[CH:38][CH:39]=2)[CH2:34]1>C(O)C>[CH3:1][S:2]([NH:5][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[O:27][CH2:28][CH:29]([OH:31])[CH2:30][NH:32][CH:33]1[CH2:42][CH2:41][C:40]2[C:35](=[CH:36][C:37]([O:43][CH2:44][C:45]([N:47]3[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]3)=[O:46])=[CH:38][CH:39]=2)[CH2:34]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N(c1cc(OCC2CO2)ccc1OCc1ccccc1)S(C)(=O)=O
Reactant: NC1CCc2ccc(OCC(=O)N3CCCCC3)cc2C1
Solvent: CCO
Product: CS(=O)(=O)Nc1cc(OCC(O)CNC2CCc3ccc(OCC(=O)N4CCCCC4)cc3C2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
2.34 g (0.0052 mole) of 3-(N-methylsulfonyl-N-tert-butoxycarbonylamino)-4-benzyloxy-1-(2,3-epoxypropoxy)-benzene, 71 ml of ethanol and 1.44 g (0.0052 mole) of 2-amino-7-piperidinocarbonylmethoxy-tetralin from preparation 1 (base, racemate) were heated under reflux for 8 hours. It was stirred at ambient temperature overnight and then it was heated again under reflux for a further 6 hours. The solvent was evaporated off, the residue was taken up in 40 ml of ethyl acetate and 32.1 ml of a 3N solution of hydrochloric acid in ethyl acetate were added. It was heated under reflux for 5 hours and evaporated under reduced pressure. It was taken up in water, NH4OH was added until the pH was basic, and it was extracted with ethyl acetate. It was dried, the solvent was evaporated off and the product was purified by silica gel column flash chromatography, eluting with a 9:1 methylene chloride/methanol mixture. 1.3 g of the product of the heading was obtained.
Reaction SMILES: [CH3:1][C:2]([Si:5]([O:8][C:9]([CH3:13])([CH3:12])[C:10]#[CH:11])([CH3:7])[CH3:6])([CH3:4])[CH3:3].C([Li])CCC.CN(C)[CH:21]=[O:22].C(O)(=O)C>O1CCCC1.O.CCCCCC>[CH3:4][C:2]([Si:5]([CH3:6])([CH3:7])[O:8][C:9]([CH3:13])([CH3:12])[C:10]#[C:11][CH:21]=[O:22])([CH3:1])[CH3:3]
Reactant: CN(C)C=O
Reactant: C#CC(C)(C)O[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C#CC=O)O[Si](C)(C)C(C)(C)C
Temperature: -20 °C
Reaction time: 0.08 h
Yield: 85.5 %

Procedure:
To a solution of 50.0 g (252 mmol) (1,1-dimethylethyl)[(1,1-dimethyl-2-propynyl)oxy]dimethylsilane in 200 mL of tetrahydrofuran (THF) at -70° C. was added 112 mL (280 mmol) of 2.5M butyl lithium (BuLi) in hexanes dropwise over 25 min., keeping the temperature below -55° C. The mixture was stirred for 5 minutes. Then, 50 mL of dimethylformamide (DMF) was added dropwise over 10 minutes. After 15 minutes, the reaction was quenched by the addition of 32 mL of acetic acid (560 mmol). After the mixture was allowed to warm to -20° C., 200 mL of hexane and 200 mL of water were added. The aqueous layer was back-extracted with 100 mL of hexane. The combined organic layers were washed with 200 mL of saturated aqueous NH4Cl solution and then with 200 mL of brine. After drying over sodium sulfate, the solution was concentrated to dryness. Then the residue was distilled through a 10-cm Vigreaux column to give 48.8 g (85.5% yield) of 4-[[(1,1-dimethylethyl) dimethylsilyl]oxy]-4methyl-2-pentynal: bp 50° C. (0.5 mm Hg).