Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21]C)[CH:18]=[C:17]2[C:4]=1[C@H:5]1[C@H:14]([CH2:15][S:16]2(=[O:24])=[O:23])[C@:13]2([CH3:25])[C@H:8]([C:9]([CH3:27])([CH3:26])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1.B(Br)(Br)Br.Cl[CH2:33]Cl>>[OH:21][C:19]1[CH:18]=[C:17]2[C:4]([C@@:5]3([CH3:33])[C@H:14]([CH2:15][S:16]2(=[O:24])=[O:23])[C@:13]2([CH3:25])[C@H:8]([C:9]([CH3:27])([CH3:26])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]3)=[C:3]([O:2][CH3:1])[CH:20]=1
Reactant: COc1cc(OC)c2c(c1)S(=O)(=O)C[C@H]1[C@H]2CC[C@H]2C(C)(C)CCC[C@]12C
Reactant: ClCCl
Agent: BrB(Br)Br
Product: COc1cc(O)cc2c1[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2(=O)=O
Reaction time: 60 h
Yield: 60 %

Procedure:
To a suspension of compound 23 (5.00 g, 12.3 mmol) in dichloromethane (20 mL) at 0° C. under argon was slowly added boron tribromide (1.0 M in DCM, 12.5 mL, 12.5 mmol). The mixture was stirred for 60 h then concentrated. The residue was dissolved in ethyl acetate (50 mL), quenched with water (250 mL) and extracted with ethyl acetate (2×200 mL). The organic layer was washed with brine (2×250 mL) then dried (MgSO4) and concentrated to afford a brown foam. The crude product was purified by column chromatography on silica gel (hexanes:ethyl acetate, 2:1) to afford compound 57 (2.90 g, 60%) as a pale solid. 1H NMR (CDCl3): δ 7.00 (d, J=2.6 Hz, 1H), 6.54 (d, J=2.5 Hz, 1H), 6.20 (s, 1H), 3.79 (s, 3H), 3.36-3.16 (m, 3H), 2.27 (d, J=11.4 Hz, 1H), 1.72-1.00 (m, 10H), 1.38 (s, 3H), 0.95 (s, 3H), 0.86 (s, 3H), 0.83 (s, 3H). 13C NMR (CDCl3): δ 159.7, 157.0, 139.3, 127.8, 105.4, 102.4, 56.2, 56.1, 53.4, 46.3, 41.9, 39.8, 39.0, 38.1, 33.7, 33.5, 21.7, 19.2, 19.1, 18.8, 17.8, 17.7. MS m/z 393 (C22H32O4S+H+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)[N:8]3[CH2:21][CH2:22][N:23]=[C:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[CH2:25][CH2:26][CH2:27][S:28]([N:31]([CH3:33])[CH3:32])(=[O:30])=[O:29]>>[CH3:32][N:31]([CH3:33])[S:28]([CH2:27][CH2:26][CH2:25][O:1][C:2]1[C:11]2[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)[N:8]3[CH2:21][CH2:22][N:23]=[C:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:30])=[O:29]
Reactant: CN(C)S(=O)(=O)CCCCl
Reactant: O=C(NC1=Nc2c(O)cccc2C2=NCCN12)c1cccnc1
Product: CN(C)S(=O)(=O)CCCOc1cccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21

Procedure:
The procedure used for the preparation of Example 1 was used to prepare the title compound from N-(7-hydroxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (Intermediate C) and 3-chloro-N,N-dimethylpropane-1-sulfonamide (Intermediate F). High vacuum drying at 60° C. gave the title compound (44 mg, 39%): HPLC MS RT=0.68 min, MH+=457.3; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.27 (2H, bs), 2.84 (6H, s), 3.36-3.37 (2H, m), 4.31 (2H, bs), 4.43 (2H, bs), 4.62 (2H, bs), 7.59-7.61 (1H, m), 7.71 (1H, bs), 7.83-7.86 (1H, m), 7.97-7.98 (1H, m), 8.89 (1H, bs), 9.00 (1H, m), 9.47 (1H, bs).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]2[N:29]=[C:28]([C:30]([OH:32])=O)[O:27][N:26]=2)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.[NH2:63][C@@H:64]([CH3:81])[CH2:65][N:66]1[CH:70]=[CH:69][C:68]([C:71]2[CH:78]=[C:77]([F:79])[C:74]([C:75]#[N:76])=[C:73]([Cl:80])[CH:72]=2)=[N:67]1>ClCCl>[Cl:80][C:73]1[CH:72]=[C:71]([C:68]2[CH:69]=[CH:70][N:66]([CH2:65][C@@H:64]([NH:63][C:30]([C:28]3[O:27][N:26]=[C:25]([C:23]4[N:22]=[CH:21][N:20]([C:1]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[CH:24]=4)[N:29]=3)=[O:32])[CH3:81])[N:67]=2)[CH:78]=[C:77]([F:79])[C:74]=1[C:75]#[N:76]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1nc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)no1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1nc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)no1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Into a flask containing 3-(1-trityl-1H-imidazol-4-yl)-1,2,4-oxadiazole-5-carboxylic acid (0.148 g, 0.350 mmol) and anhydrous HOBt (0.047 g; 0.350 mmol), dichloromethane (2 ml), DIPEA (0.122 ml; 0.700 mmol) and EDCI (0.067 g; 0.350 mmol) were added and stirred for 10 min at RT. (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.100 g, 0.269 mmol) dissolved in 2 ml of dichloromethane was added and the resulting mixture stirred overnight. Next day the temperature was raised to 50° C. and more EDCI (0.067 g; 0.350 mmol) was added. The reaction mixture was allowed to react with stirring for 4 h. DCM was added and the organic layer was extracted with 1M Na2CO3 and water. The organic layer was then evaporated and the residue purified with flash chromatography. LC-MS: [M+1]=684.133.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][C:3]=1[F:10].[F:11][CH:12]([F:15])[CH2:13][NH2:14].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:14][CH2:13][CH:12]([F:15])[F:11])=[CH:4][C:3]=1[F:10]
Reactant: Fc1cc(CCl)cnc1Cl
Reactant: NCC(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Fc1cc(CNCC(F)F)cnc1Cl
Reaction time: 16 h
Yield: 57 %

Procedure:
At 45° C., 520 mg (2.89 mmol) of 6-chloro-3-chloromethyl-5-fluoropyridine (Va-4), 1.05 ml (14.44 mmol) of 2,2-difluoroethylamine and 400 μl (2.89 mmol) of triethylamine in 50 ml of acetonitrile are stirred for about 48 hours. During the reaction, after about 16 hours and 32 hours, a further 0.42 ml (5.78 mmol) of 2,2-difluoroethylamine are added in each case. The reaction mixture is concentrated under reduced pressure and then taken up in 1 N aqueous hydrochloric acid and washed with ethyl acetate. The aqueous phase is made alkaline using 2.5 N aqueous sodium hydroxide solution and extracted repeatedly with ethyl acetate. Drying of the combined organic phases over sodium sulphate and concentration under reduced pressure gives 370 mg (57% of theory) of N-[(6-chloro-5-fluoropyridin-3-yl)methyl]-2,2-difluoroethylamine.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([NH:17][CH2:18][CH3:19])([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH2:18]([NH:17][C:11]1([C:14]([NH2:16])=[O:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH3:19]
Reactant: CCNC1(C(N)=O)CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCNC1(C(N)=O)CCNCC1

Procedure:
To a solution of 1-benzyl-4-ethylaminopiperidine-4-carboxylic acid amide (I-1A-1e; 7.39 g, 28.3 mmol) in methanol (100 ml) was added 20% Pd(OH)2 on carbon (50% water; 1.48 g). The mixture was placed on a Parr® shaker and was reduced (50 psi H2) at room temperature overnight. The mixture was filtered through a pad of Celite®, and then concentrated to give a colorless solid I-1A-if (4.84 g, quantitative): +APcl MS (M+1) 172.2; 1H NMR (400 MHz, CD2Cl2) δ 2.89 (ddd, J=12.9, 8.7, 3.3 Hz, 2H), 2.75 (ddd, J=12.9, 6.6, 3.7 Hz, 2H), 2.45 (q, J=7.2 Hz, 2H), 1.95 (ddd, J=13.7, 8.3, 3.7 Hz, 2H), 1.55 (ddd, J=13.7, 6.6, 3.3 Hz, 2 h), 1.08 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[NH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([NH:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=[N+]([O-])c1cnc2ccsc2c1N[C@H]1CC[C@H](O)CC1
Temperature: 90 °C

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (0.47 g, 2.2 mmol) (Example 1, step 2), trans-4-aminocyclohexanol (from Aldrich, 0.50 g, 4.4 mmol) and N,N-diisopropylethylamine (1.1 mL, 6.6 mmol) in isopropyl alcohol (7.4 mL) was heated at 90° C. for 2 h. The reaction mixture was concentrated and purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give the desired product (0.266 g, 41%). LCMS calculated for C13H16N3O3S (M+H)+: m/z=294.1. Found: 294.0.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][N+:8]([O-:11])=[C:7]([CH3:12])[C:6]=1[CH3:13].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:12][C:7]1[C:6]([CH3:13])=[C:5]([S:4][CH2:3][CH2:2][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:10]=[CH:9][N+:8]=1[O-:11]
Reactant: C1COCCN1
Reactant: Cc1c(SCCCl)cc[n+]([O-])c1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1c(SCCN2CCOCC2)cc[n+]([O-])c1C

Procedure:
4-(2-Chloroethylthio)-2,3-dimethylpyridine-N-oxide (6 g) was dissolved in a mixed solution of dimethylformamide-toluene (1:1) and thereto were added potassium carbonate (4.3 g), potassium iodide (4.4 g) and morpholine (1.9 ml). The mixture was reacted at 50-55° C. for 12 hours. After the completion of the reaction, inorganic matters were filtered off and the solvent was distilled away. Water was added to the residue and the mixture was extracted with chloroform. After drying over anhydrous magnesium sulfate, the chloroform was distilled away and the obtained residue was purified by silica gel column chromatography to give 3.4 g of 2,3-dimethyl-4-(2-morpholinoethylthio)pyridine-N-oxide.
Reaction SMILES: Cl.C(OC([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:25]2[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]2)=[CH:10]1)=O)(C)(C)C>C(OCC)(=O)C>[N:25]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[S:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][CH:10]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2Sc2cn(C(=O)OC(C)(C)C)c3ccccc23)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc(N2CCNCC2)c(Sc2c[nH]c3ccccc23)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3 M HCl-gas in dry ethyl acetate (3 mL) was added to 3-[2-(4-tert-butoxycarbonyl-piperazin-1-yl)-phenylsulfanyl]-indole-1-carboxylic acid tert-butyl ester. The solution was stirred for 1 h at 0° C. and evaporated under vacuum. The crude product was purified by preparative LC-MS. The isolated product was submitted for testing as DMSO solution.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[CH2:9]([O:16][C:17]([CH2:19][CH2:20][C:21](O)=[O:22])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH2:9]([O:16][C:17]([CH2:19][CH2:20][C:21]([O:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1)=[O:22])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)CCC(=O)OCc1ccccc1
Reactant: O=c1cc(O)cc[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(CCC(=O)Oc1cc[nH]c(=O)c1)OCc1ccccc1
Yield: 22.9 %

Procedure:
To a solution of 1.00 g of 4-hydroxy-2-pyridone and 2.00 g of 3-benzyloxycarbonylpropionic acid in 30 ml of dimethylformamide was added at room temperature 1.90 g of N,N'-dicyclohexylcarbodiimide with stirring and the mixture was stirred overnight. The crystals formed were filtered off and the filtrate was concentrated. The concentrate was dissolved in 50 ml of ethyl acetate and washed with 20 ml of water three times. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated. The concentrate was then subjected to silica gel column chromatography using as an eluent 2% methanol-chloroform, giving 0.62 g of the title compound in a yield of 23%.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:4].[NH2:25][CH2:26][C:27]([OH:29])=[O:28]>>[C:23]([C:7]1[C:8]2[C:13](=[C:12]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:10][CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cccc(Oc3ccccc3)c2c1O
Reactant: NCC(=O)O
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Oc3ccccc3)cccc12

Procedure:
The title compound was synthesized from 1-Cyano-4-hydroxy-5-phenoxy-isoquinoline-3-carboxylic acid methyl ester and glycine in analogy to example 1b; MS-(+)-ion: M+1=363.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24](O)=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][CH2:52][CH2:53][CH2:54][OH:55].CCN(C(C)C)C(C)C>C(#N)C.O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([NH:51][CH2:52][CH2:53][CH2:54][OH:55])=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: NCCCO
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NCCCO)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
To a DMF (2 mL) suspension of (R)-5-(2-(5-fluoro-2-methoxy pyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation B, 250 mg, 0.700 mmol) and HATU (319 mg, 0.840 mmol) cooled to 0° C. was added 3-aminopropan-1-ol (0.0642 mL, 0.840 mmol) drop-wise, resulting in a clear yellowish solution. After dropwise addition of DIEA (0.366 mL, 2.10 mmol), ice bath was removed and reaction was stirred at ambient temperature for 1 hour. The reaction was directly purified on reverse phase column chromatography (Biotage SP4 system, C-18 25+M column, 0 to 54% Acetonitrile/water), to provide the product as white solid (200 mg, 69% yield). MS (apci) m/z=415.1 (M+H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][C:13]1[CH:14]=[C:9]([O:7][CH2:3][C:4]#[C:5][CH3:6])[N:10]=[CH:11][N:12]=1
Reactant: CC#CCO
Reactant: Clc1cc(Cc2ccccc2Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(Cc2ccccc2Cl)ncn1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
In 2 ml of tetrahydrofuran was suspended 0.05 g of sodium hydride (60% in oil), to which 0.6 ml of a tetrahydrofuran solution containing 0.07 g of 2-butyn-1-ol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, to which 0.6 ml of a tetrahydrofuran solution containing 0.2 g of 4-chloro-6-(2-chlorobenzyl)pyrimidine was slowly added dropwise at room temperature, followed by stirring for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.19 g of 4-(2-chlorobenzyl)-6-(2-butynyloxy)pyrimidine (the present compound (89)).
Reaction SMILES: [Na].C1(C)C=CC=CC=1.[CH3:9][O:10][CH:11]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:12]([O:14]C)=O>C(O)(=O)C>[CH3:9][O:10][CH:11]1[CH2:16][CH2:17][CH:18]([C:19]([O:21][CH3:22])=[O:20])[C:12]1=[O:14]
Reactant: COC(=O)CCCC(OC)C(=O)OC
Agent: [Na]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)C1CCC(OC)C1=O
Temperature: 60 °C
Yield: 54.2 %

Procedure:
1.38 g of sodium metal was added to 100 ml of toluene, and the mixture was heated to 60° C. 10.2 g of dimethyl α-methoxyadipate [prepared as described in step (a) above] were then added dropwise to the hot mixture. The mixture was then heated under reflux for 8 hours, after which it was cooled to room temperature and added to a 10% w/v aqueous solution of acetic acid. The organic layer was separated, washed first with a saturated aqueous solution of sodium carbonate and then with water, and then dried over anhydrous sodium sulfate. The solvent was then evaporated off under reduced pressure, and the residue was distilled, to give 4.66 g of the title compound as a pale oil, boiling at 83°-87° C./3 mm Hg (about 400 Pa).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([S:24][CH3:25])[C:15]([NH:17][C:18]([CH2:22][OH:23])([CH3:21])[C:19]#[CH:20])=[O:16])=[CH:8][CH:7]=2)#[CH:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([S:24][CH3:25])[C:15]([NH:17][C:18]([CH:22]=[O:23])([CH3:21])[C:19]#[CH:20])=[O:16])=[CH:8][CH:7]=2)#[CH:2]
Reactant: C#Cc1cnc2ccc(OC(SC)C(=O)NC(C)(C#C)CO)cc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: C#Cc1cnc2ccc(OC(SC)C(=O)NC(C)(C#C)C=O)cc2c1
Reaction time: 2 h

Procedure:
2-(3-Ethynyl-quinolin-6-yloxy)-N-(1-hydroxymethyl-1-methylprop-2-ynyl)-2-methylsulfanyl acetamide (0.513 g) in dichloromethane (25 ml) was treated with Dess-Martin periodinane (0.737 g). The reaction mixture was stirred at 0.646 g for 2 hrs and then treated with sat. aqueous NaHCO3 and sat. aqueous sodium thiosulphate. The organic layer was washed thrice with sat. aqueous. NaHCO3. After separation, the organic phase was dried over sodium sulphate, filtered and evaporated to yield crude 2-(3-ethynyl-quinolin-6-yloxy)-N-(1-formyl-1-methyl-prop-2-ynyl)-2-methylsulfanyl acetamide which was used as such in Stage 6. 1H NMR (CDCl3) δ ppm: 9.40 (1H, s); 8.86 (1H, d); 8.22 (1H, d); 8.07 (1H, d); 7.52-7.49 (1H, m); [{7.49 (s br), 7.44 (s br) 1H}, isomer A and isomer B]; 7.26 (1H, m); [{5.74 (s), 5.72 (s) 1H}, isomer A and isomer B]; 3.29 (1H, s); 2.54 (1H, s); [{2.23 (s), 2.21 (s) 3H}, isomer A and isomer B]; 1.79 (3H, s).
Reaction SMILES: [C:1](=[O:12])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])OC(C)(C)C.[CH3:13][O:14][C:15]([C:17]1[CH:25]=[C:24]2[C:20]([CH2:21][CH2:22][NH:23]2)=[C:19]([O:26][CH3:27])[CH:18]=1)=[O:16].C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:13][O:14][C:15]([C:17]1[CH:25]=[C:24]2[C:20]([CH2:21][CH2:22][N:23]2[C:1]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:12])=[C:19]([O:26][CH3:27])[CH:18]=1)=[O:16]
Reactant: COC(=O)c1cc2c(c(OC)c1)CCN2
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(OC)c2c(c1)N(C(=O)OC(C)(C)C)CC2
Yield: 47 %

Procedure:
Di-tert-butyl carbonate (2.9 g, 13.5 mmol, 1 equiv.) was added to a stirred mixture of 4-methoxy-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester (2.8 g 13.5 mmol, 1 equiv.) and diisopropyl ethyl amine (4.7 mL, 27 mmol, 2 equiv.) in tetrahydrofuran (30 mL) and the mixture was heated at reflux for 16 hours. The solvent was evaporated under vacuum and the residue purified by column chromatography (SiO2, 1:8 EtOAc:heptane). The fractions were combined to afford 4-methoxy-2,3-dihydro-indole-1,6-dicarboxylic acid 1-tert-butyl ester 6-methyl ester, 1.96 g (47% yield). δH (250 MHz; d6-DMSO) 7.80 (1H, s), 7.10 (1H, s), 3.96 (2H, t), 3.78 (6H, s), 3.03 (2H, t), 1.45 (9H, m).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[N:3]=1.[NH2:15][CH:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1.C(N(CC)C(C)C)(C)C.Cl.O1CCOCC1>CS(C)=O>[NH:19]1[CH2:20][CH2:21][CH:16]([NH:15][C:2]2[CH:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[N:3]=2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: OCCc1cc(Cl)nc(C(F)(F)F)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: OCCc1cc(NC2CCNCC2)nc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 2.33 h

Procedure:
A mixture of 2-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]ethanol (0.085 g, 0.38 mmol, from Step 1), tert-butyl 4-aminopiperidine-1-carboxylate (0.30 g, 1.5 mmol) and N,N-diisopropylethylamine (0.16 mL, 0.94 mmol) in dimethyl sulfoxide (0.86 mL) was heated in the microwave to 100° C. for one hour, then to 140° C. for 140 minutes. The reaction mixture was concentrated. The residue was dissolved in 1,4-dioxane (2.8 mL) and was treated with 4.0 M hydrogen chloride in dioxane (2.8 mL, 11 mmol). After stirring overnight, solvent was removed in vacuo. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH) afforded two major fractions, the desired product was the first eluting of the peaks having the desired mass (16 mg, 15%). LCMS (M+H)+: 290.1.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.FC(F)(F)C(O)=O.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:38]=[C:39]([CH:43]=[C:44]([S:46]([F:51])([F:50])([F:49])([F:48])[F:47])[CH:45]=2)[C:40](O)=[O:41])[CH2:33][CH2:32]1>>[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:38]=[C:39]([CH:43]=[C:44]([S:46]([F:51])([F:47])([F:48])([F:49])[F:50])[CH:45]=2)[C:40]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]3[C:16]4[N:12]([N:13]=[C:14]([C:17]5[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=5)[CH:15]=4)[CH:11]=[CH:10]3)[CH:4]=2)=[O:41])[CH2:33][CH2:32]1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Reactant: CN1CCN(c2cc(C(=O)O)cc(S(F)(F)(F)(F)F)c2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)c2cc(N3CCN(C)CC3)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
50 mg (0.17 mmol) of the compound of Example 6A and 79.6 mg (0.17 mmol) of the compound of Example 17A were reacted and worked up analogously to the procedure of Example 16. This gave 82 mg (77% of theory) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].Cl[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][CH3:31])[CH2:19][CH2:18]1.O>>[CH2:30]([O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][O:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][CH2:6][C:7]3=[O:12])[CH2:18][CH2:19]1)[CH3:31]
Reactant: O=C1CCCc2c(O)cccc21
Reactant: CCOc1ccccc1N1CCN(CCCCl)CC1
Solvent: O
Product: CCOc1ccccc1N1CCN(CCCOc2cccc3c2CCCC3=O)CC1
Yield: 86 %

Procedure:
from 5-hydroxy-1-oxotetraline and 1-(3-chloropropyl)-4-(2-ethoxyphenyl)-piperazine; yield 86% of theory; the hydrochloride, after recrystallization from water, contained, after drying, 0.406 mol water; m.p. 196°-197°C.
Reaction SMILES: [CH:1]1([CH:7]([CH3:11])[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:12]=[C:13]([CH3:15])[CH3:14].S(=O)(=O)(O)O>CCOCC>[CH:1]1([CH:7]([CH3:11])[C:8]([O:10][C:13]([CH3:15])([CH3:14])[CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C(C)C
Reactant: CC(C(=O)O)C1CCCCC1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CC(C(=O)OC(C)(C)C)C1CCCCC1
Temperature: 0 °C
Reaction time: 40 h
Yield: 11 %

Procedure:
Into a 500 ml round bottom flask 30 g of 2-cyclohexylpropionic acid and 200 ml of ether were charged and cooled to 0° C. After 100 g of isobutene gas was introduced, 0.5 g of sulfuric acid was charged into the mixture, the mixture was then stirred at 0° C. for 40 hours. The reaction mixture was washed with water and distilled under reduced pressure to obtain 4.5 g of tert-butyl 2-cyclohexylpropionate having a woody and floral odor (yield: 11%, purity: 98.7%).