Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([N:28]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH2:29][CH2:30][CH2:31][N:32]([CH2:36][CH2:37][OH:38])[CH2:33][CH2:34][OH:35])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(OC(=O)C)C>[CH2:39]([N:28]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:29][CH2:30][CH2:31][N:32]([CH2:33][CH2:34][O:35][C:8](=[O:9])[NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:36][CH2:37][O:38][C:8](=[O:9])[NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)CCCN(CCO)CCO
Reactant: O=C=Nc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)CCCN(CCOC(=O)Nc1ccccc1)CCOC(=O)Nc1ccccc1

Procedure:
Phenyl isocyanate (3.85 g.) is added to a warm solution of N,N-dioctadecyl-N',N'-bis(2-hydroxyethyl)-1,3-propanediamine (5.0 g.) in ethylacetate (20 ml.) and the mixture heated to reflux for one hour. The mixture is cooled, then taken to dryness under reduced pressure. The residue is triturated with carbon tetrachloride, filtered, and the filtrate evaporated to dryness. Ethyl acetate (25 ml.) is then added, the mixture cooled, filtered, washed with ethylacetate and dried in vacuo; m.p. 54°-6° C.
Reaction SMILES: [ClH:1].[CH2:2]([NH:10][C:11](=[O:25])[C@H:12]([C@H:21]([CH2:23][CH3:24])[CH3:22])[NH:13]C(OC(C)(C)C)=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CCCCCC>CCOC(C)=O>[ClH:1].[CH2:2]([NH:10][C:11](=[O:25])[C@H:12]([C@H:21]([CH2:23][CH3:24])[CH3:22])[NH2:13])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCCc1ccccc1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC[C@H](C)[C@H](N)C(=O)NCCc1ccccc1
Yield: 100 %

Procedure:
Hydrogen chloride gas was bubbled into a solution of N-t-butoxycarbonyl-L-isoleucine-phenethylamide (3.1 g, 9.3 mmol) in EtOAc (200 mL) at -20° C. in a dry ice-acetone bath until TLC (EtOAc: hexane, 1:3) indicated complete loss of starting material. The solution was concentrated to dryness to give 2.5 g (100%) of the title compound, which was used without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](N2CCN3C4CCCCC=4C=C3C2=O)=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[N:27]1[CH2:39][CH2:38][N:30]2[C:31]3[CH2:32][CH2:33][CH2:34][CH2:35][C:36]=3[CH:37]=[C:29]2[C:28]1=[O:40])(=[O:3])[CH3:2].Br[C:42]1[CH:43]=[C:44]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([CH:57]3[CH2:61][CH2:60][CH2:59][N:58]3[CH3:62])=[CH:53][N:52]=2)[C:45](=[O:49])[N:46]([CH3:48])[CH:47]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.C(Cl)Cl.CO>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:27]2[CH2:39][CH2:38][N:30]3[C:35]4[CH2:34][CH2:33][CH2:32][CH2:31][C:36]=4[CH:37]=[C:29]3[C:28]2=[O:40])=[CH:8][C:9]([F:26])=[CH:10][C:11]=1[C:42]1[CH:43]=[C:44]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([CH:57]3[CH2:61][CH2:60][CH2:59][N:58]3[CH3:62])=[CH:53][N:52]=2)[C:45](=[O:49])[N:46]([CH3:48])[CH:47]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(N2CCn3c(cc4c3CCCC4)C2=O)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CN1CCCC1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
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: ClCCl
Solvent: CO
Solvent: COCCOC
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CCCN4C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 62.6 %

Procedure:
Following Example 121b, 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d (338 mg, 0.7 mmol), 202a (181 mg, 0.5 mmol), 1M sodium carbonate solution (2 mL, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol) and 1,2-dimethoxyethane (5 mL) were reacted. Work-up and flash column chromatography (silica, 3:1 methylene chloride/methanol) give a mixture (200 mg) of 4-fluoro-2-(1-methyl-5-(5-(1-methylpyrrolidin-2-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzyl acetate and 202 as a yellow residue.
Reaction SMILES: C(OC1C=CC=CC=1OCC1OC1)C#C.Cl.[CH2:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH:18]1[NH:27]CC(O)CC1C=CC=CC=1OCC#C>C(O)C>[NH2:27][CH:18]1[CH2:19][CH2:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17]1
Reactant: C#CCOc1ccccc1CC(O)CNC1CCc2ccccc2C1
Agent: C#CCOc1ccccc1OCC1CO1
Agent: Cl
Solvent: CCO
Product: NC1CCc2ccccc2C1

Procedure:
Following the procedure of Example 27, but starting from 2-propargyloxy-l-(2,3-epoxypropoxy)benzene (2.04 g) and 2-aminotetralin in absolute ethanol (30 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-propargyloxyphenyl)propanamine hydrochloride is obtained, m.p. 129°-130° C. (Ex. 85).
Reaction SMILES: [CH2:1]([Si:4]([Cl:7])(Cl)Cl)[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:15][C@H:16]([NH:25][CH3:26])[C@@H:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:1]([Si:4]1([Cl:7])[N:25]([CH3:26])[C@@H:16]([CH3:15])[C@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:24]1)[CH:2]=[CH2:3]
Reactant: CN[C@@H](C)[C@@H](O)c1ccccc1
Reactant: C=CC[Si](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC[Si]1(Cl)O[C@@H](c2ccccc2)[C@H](C)N1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
To a cooled (0° C.) solution of allyltrichlorosilane (101 mL, 0.696 mol) in methylene chloride (1.8 L) under argon was added triethylamine (170 mL, 1.21 mol). (1S,2S)-pseudoephedrine (100 g, 0.605 mol) was then added portionwise over 30 min, to maintain internal temperature below 15° C. After the addition was complete the mixture was stirred for 12 hours at ambient temperature. The methylene chloride was removed by distillation and the residue was diluted with pentane (1.5 L). The mixture was vigorously stirred for 12 hours to ensure complete precipitation of the triethylamine salts. Filtration of the resulting suspension through a pad of celite and concentration of the filtrate by distillation afforded the crude product as a pale yellow oil. Purification by distillation under reduced pressure (bp˜120 C, 5 mm Hg) provided 149 g (92%) of (4S, 5S)-2-Allyl-2-chloro-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine as a ˜2:1 mixture of diastereomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH3:32])[C:16]([NH:18][C:19]2[CH:31]=[CH:30][C:22]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:21][CH:20]=2)=[O:17])[C:11](=[O:33])[CH:10]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH3:32])[C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:30][CH:31]=2)=[O:17])[C:11](=[O:33])[CH:10]=1
Reactant: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1ccc(-c2cc(Cl)ccc2Cl)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)Nc1ccc(C(=O)O)cc1)n1ccc(-c2cc(Cl)ccc2Cl)cc1=O

Procedure:
83 mg (0.17 mmol) of tert-butyl 4-({2-[4-(2,5-dichlorophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate (racemate) (Example 2.9C) were hydrolysed with TFA according to General Method 2. Yield: 21 mg (purity 88%, 23% of theory)
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:32][O:33][C:34]1[CH:42]=[CH:41][C:37]([CH2:38][CH2:39]O)=[CH:36][CH:35]=1.[C:43]1(=[O:49])[NH:47][C:46](=[O:48])[CH:45]=[CH:44]1>>[CH3:32][O:33][C:34]1[CH:42]=[CH:41][C:37]([CH2:38][CH2:39][N:47]2[C:43](=[O:49])[CH:44]=[CH:45][C:46]2=[O:48])=[CH:36][CH:35]=1
Reactant: O=C1C=CC(=O)N1
Reactant: COc1ccc(CCO)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(CCN2C(=O)C=CC2=O)cc1

Procedure:
Reagents: Ph3P (1.31 g, 5 mmol), DEAD (0.8 ml, 5 mmol), p-methoxyphenethyl alcohol (1.2 g, 7.5 mmol) and maleimide (0.48 g, 5 mmol).
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:11][N:12]1[C:16]([CH3:17])=[CH:15][C:14]([NH2:18])=[N:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:8][C:6]1[CH:7]=[C:2]([NH:18][C:14]2[CH:15]=[C:16]([CH3:17])[N:12]([CH3:11])[N:13]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Cc1cc(N)nn1C
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(Br)cn(C)c2=O)nn1C
Temperature: 25 °C
Yield: 56 %

Procedure:
A 250-mL single-necked round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 3,5-dibromo-1-methylpyridin-2(1H)-one (1.50 g, 5.62 mmol), 1,5-dimethyl-3-amino-1H-pyrazole (625 mg, 5.62 mmol), cesium carbonate (5.48 g, 16.8 mmol) and 1,4-dioxane (36 mL). After bubbling nitrogen through the resulting solution for 30 min, Xantphos (553 mg, 0.955 mmol) and tris(dibenzylideneacetone)dipalladium(0) (625 mg, 0.562 mmol) were added and the reaction mixture was heated at reflux for 16 h. The reaction mixture was cooled to room temperature and the resulting precipitate was filtered off. The filter cake was washed with methylene chloride (approximately 20 mL). The resulting filtrate was then concentrated under reduced pressure and purified by column chromatography to afford 105a (935 mg, 56%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.84 (s, 1H), 7.31 (s, 1H), 6.86 (s, 1H), 5.65 (s, 1H), 3.71 (s, 3H), 3.57 (s, 3H), 2.23 (s, 3H); MS (ESI+) m/z 297.0 (M+H).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[N:8]([OH:13])[C:7]([CH3:15])([CH3:14])[CH2:6]1)(=[O:3])[CH3:2].[CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:27])[CH3:26])[C:20]=1[N:28]=[C:29]=[N:30][C:31]1[C:36]([CH:37]([CH3:39])[CH3:38])=[CH:35][CH:34]=[CH:33][C:32]=1[CH:40]([CH3:42])[CH3:41])([CH3:18])[CH3:17]>O1CCCC1>[CH:40]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([CH:37]([CH3:39])[CH3:38])[C:31]=1[NH:30][C:29]([O:13][N:8]1[C:9]([CH3:12])([CH3:11])[CH2:10][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][C:7]1([CH3:15])[CH3:14])=[N:28][C:20]1[C:19]([CH:16]([CH3:18])[CH3:17])=[CH:24][CH:23]=[CH:22][C:21]=1[CH:25]([CH3:27])[CH3:26])([CH3:42])[CH3:41]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=Nc1c(C(C)C)cccc1C(C)C
Reactant: CC(=O)OC1CC(C)(C)N(O)C(C)(C)C1
Solvent: C1CCOC1
Product: CC(=O)OC1CC(C)(C)N(OC(=Nc2c(C(C)C)cccc2C(C)C)Nc2c(C(C)C)cccc2C(C)C)C(C)(C)C1
Temperature: 52 °C

Procedure:
To a solution of 4-acetoxy-1-hydroxy-2,2,6,6-tetramethylpiperidine (2.63 g, 12.2 mmol, [prepared as described in Example 1] in tetrahydrofuran (10 ml) is added bis(2,6-diisopropylphenyl)carbodiimide (4.52 g, 12.5 mmol) and the solution is heated to 52° C. under argon for 20 hours. The reaction mixture is evaporated and the residue chromatographed on silica gel with hexane-ethylacetate (5:1). The pure fractions are recrystallized from hexane to afford 1.87 g of the compound 10 as colorless crystals, mp. 144-147° C.
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[CH:7][C:6]=1[Cl:14])=O.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[C:24]1([C:27](=[S:29])[NH2:28])[CH2:26][CH2:25]1>CN(C)C=O.C(OCC)(=O)C>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[C:24]1([C:27]2[S:29][C:2]([CH3:15])=[C:3]([C:5]3[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[CH:7][C:6]=3[Cl:14])[N:28]=2)[CH2:26][CH2:25]1
Reactant: NC(=S)C1(c2c(F)cccc2Cl)CC1
Reactant: COc1cc(Cl)c(C(=O)C(C)Br)cc1C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(-c2nc(C3(c4c(F)cccc4Cl)CC3)sc2C)cc1C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-Bromo-1-(2-chloro-4-methoxy-5-methly-phenyl)-propan-1-one (254 mg, 0.87 mmol) and 1-(2-Chloro-6-fluoro-phenyl) cyclopropane carbothioic acid amide (200 mg, 0.87) mmol) were dissolved in dimethlyformamide (DMF) (2.9 mL). The reaction was heated with stirring to 80° C. overnight. The mixture was then cooled, diluted with ethyl acetate and washed three times with water and once with brine. The organic layer was separated, dried with sodium sulfate and concentrated in vacuo. The crude product was then chromatographed on silica using an ethyl acetate/hexane gradient resulting in a pale green-yellow solid. Yield: 110 mg (18%). [MH]+422.0. 1H NMR (300 MHz, CDCl3) •1.54 (m, cyclopropyl, 2H), 2.11 (m, cyclopropyl, 2H), 2.27 (s, CH3, 3H), 2.28 (s, CH3, 3H), 3.93 (s, —OCH3, 3H), 6.97 (s, Ar, 1H), 7.15 (m, Ar, 1H), 7.35 (s, Ar, 1H), 7.37 (m, Ar, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14](O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.P(Br)(Br)(Br)(Br)[Br:22]>>[Br:22][CH:14]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:2]([Cl:1])[CH:3]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(O)c1ccc(C2CCCCC2)c(Cl)c1
Reactant: BrP(Br)(Br)(Br)Br
Product: CCOC(=O)C(Br)c1ccc(C2CCCCC2)c(Cl)c1

Procedure:
To 15.0 g. (0.0476 moles) of ethyl 3-chloro-4-cyclohexylphenylglycolate there is added slowly with stirring at 40°-50° C 23 g. (0.053 moles) of phosphorus pentabromide. The mixture is stirred at room temperature for 16 hours, then diluted with 70 ml. of petroleum ether, and poured into 125 ml. of ice-cold water. The organic phase is separated, washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo to obtain ethyl α-bromo-3-chloro-4-cyclohexylphenylacetate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]([OH:19])=O)[C:12]2[C:7](=[CH:8][C:9]([CH3:20])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].FC1C(O)=C(F)C(F)=C(F)C=1F.[OH:33][C@@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1.C(N1CCOCC1)C>CN(C=O)C.C(Cl)Cl.C(Cl)CCl>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]([N:36]2[CH2:37][CH2:38][C@@H:34]([OH:33])[CH2:35]2)=[O:19])[C:12]2[C:7](=[CH:8][C:9]([CH3:20])=[CH:10][CH:11]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(OCC(=O)O)c2ccc(C)cc2n1
Reactant: O[C@@H]1CCNC1
Agent: CCN1CCOCC1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)c1cc(OCC(=O)N2CC[C@@H](O)C2)c2ccc(C)cc2n1

Procedure:
To a solution of 1000 mg 4-Carboxymethoxy-7-methyl-quinoline-2-carboxylic acid methyl ester in 5 ml DMF were added 956 mg pentafluorophenol and 994 mg EDC. The mixture was stirred under exclusion of moisture until LCMS indicated complete conversion to the corresponding pentafluorophenolester. (R)-3-hydroxypyrrolidine (287 mg) was mixed with 1.3 ml N-ethylmorpholine and 5 ml DMF and this mixture added dropwise to the solution of the pentafluorophenolester. After 12 h the reaction mixture was diluted with DCM and washed with aqueous LiCl (4%) and saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica eluting with ethyl acetate/methanol gradient. Yield: 996 mg.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:7])=[N:4][NH:5][CH:6]=1.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1OB(O)O.N1C=CC=CC=1>CN(C)C=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[C:3]([CH3:7])=[N:4][N:5]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[F:8])[CH:6]=1
Reactant: OB(O)Oc1ccccc1F
Reactant: Cc1n[nH]cc1Br
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1nn(-c2ccccc2F)cc1Br
Temperature: 25 °C
Reaction time: 72 h
Yield: 8.5 %

Procedure:
580 mg of 4-bromo-3-methylpyrazole, 1.0 g of 2-fluorophenylboric acid, 3.3 g of copper acetate, 1.0 g of molecular sieves 4A, and 1.6 ml of pyridine were suspended in 8.0 ml of dimethylformamide, and the mixture was stirred at room temperature for 3 days. The obtained suspended solution was filtrated by celite, and the filtrate was diluted with ethyl acetate. Organic layer was washed with 0.5 N sodium hydride, dried with sodium sulfate, and the solvents were distilled outunder reduced pressure. The residues were purified by silicagel column chromatography (hexane:ethyl acetate=50:50) to obtain 78 mg of the above compound as a crude product.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]([C:15]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH:16]=3)=[O:14])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Cl[C:36]([O:38][CH3:39])=[O:37].N1CCCCC1>CO>[CH3:39][O:38][C:36]([NH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]([C:15]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH:16]=3)=[O:14])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1)=[O:37]
Reactant: NC1CCCc2ccc(NC(=O)c3c[nH]c4ccccc4c3=O)cc21
Reactant: COC(=O)Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNCC1
Product: COC(=O)NC1CCCc2ccc(NC(=O)c3c[nH]c4ccccc4c3=O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.5 %

Procedure:
To a solution of N-(1-aminotetralin-7-yl)-4-oxo-1H-quinoline-3-carboxamide (273-I) (65 mg, 0.20 mmol) and DIEA (52 μL, 0.29 mmol) in methanol (1 mL) was added methyl chloroformate (22 μL, 0.29 mmol). The reaction was stirred at room temperature for 1 h. LCMS analysis of the reaction mixture showed peaks corresponding to both the single and bis addition products. Piperidine (2 mL) was added and the reaction was stirred overnight after which only the single addition product was observed. The resulting solution was filtered and purified by HPLC (10-99% CH3CN—H2O) to yield the product, [7-[(4-oxo-1H-quinolin-3-yl)carbonylamino]tetralin-1-yl]aminoformic acid methyl ester (159) (27 mg, 35%). HPLC ret. time 2.68 min, 10-99% CH3CN, 5 min run; ESI-MS 392.3 m/z (MH+).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[H-].[Na+].[CH3:13][CH:14]([CH3:18])[CH2:15][CH2:16][OH:17]>>[CH3:13][CH:14]([CH3:18])[CH2:15][CH2:16][O:17][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CC(C)CCO
Agent: [H-]
Agent: [Na+]
Product: CC(C)CCOc1ccc(C(=O)O)cn1

Procedure:
6-(3-Methylbutoxy)nicotinic acid was prepared from 6-chloronicotinic acid (0.50 g), 3-methyl-1-butanol (0.36 ml) and sodium hydride (60%, 0.32 g) according to the method described in Example 54 to give the product as a white solid (0.25 g, 38%): δH (400 MHz, DMSO-d6) 12.97 (1H, m), 8.71 (1H, d, J 2.5 Hz), 8.12 (1H, dd, J 8.5, 2.5 Hz), 6.87 (1H, d, J 8.5 Hz), 4.36 (2H, t, J 7 Hz), 1.75 (1H, nonet, J 6.5 Hz), 1.62 (2H, q, J 6.5 Hz) and 0.93 (6H, d, J 6.5 Hz); HPLC (XTERRA, 20/50, 220 nm) 99% (3.90 min).
Reaction SMILES: [CH3:1][C@@H:2]1[C@:25]2([O:31][CH2:30][C@H:28]([CH3:29])[CH2:27][CH2:26]2)[O:24][C@H:4]2[CH2:5][C@@H:6]3[C@@:20]([CH3:21])([C@@H:3]12)[CH2:19][C:18](=[O:22])[C@H:17]1[C@H:7]3[CH2:8][CH2:9][C@@H:10]2[C@:15]1([CH3:16])[CH2:14][CH2:13][C@H:12]([OH:23])[CH2:11]2.[Li].N>>[CH3:1][C@@H:2]1[C@:25]2([O:31][CH2:30][C@H:28]([CH3:29])[CH2:27][CH2:26]2)[O:24][C@H:4]2[CH2:5][C@@H:6]3[C@@:20]([CH3:21])([C@@H:3]12)[CH2:19][C@@H:18]([OH:22])[C@H:17]1[C@H:7]3[CH2:8][CH2:9][C@@H:10]2[C@:15]1([CH3:16])[CH2:14][CH2:13][C@H:12]([OH:23])[CH2:11]2
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4C(=O)C[C@]3(C)[C@H]1[C@@H]2C
Agent: N
Agent: [Li]
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4[C@H](O)C[C@]3(C)[C@H]1[C@@H]2C

Procedure:
(3β,5α,25R)spirostan-3-ol-11-one (Aldrich Chemical Company, Milwaukee, Wis. or Steraloids Inc., Wilton, N.H., or see preparation G13) was converted into the title compound via reduction with lithium and ammonia according to the procedure described in J. Am. Chem. Soc., 1953, 75, 1282.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([N:15]3[CH2:18][CH:17]([OH:19])[CH2:16]3)=[O:14])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:21]1[CH:22]=[CH:23][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[N:25][CH:26]=1>>[CH:1]1([N:6]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([N:15]3[CH2:18][CH:17]([O:19][C:21]4[CH:22]=[CH:23][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[N:25][CH:26]=4)[CH2:16]3)=[O:14])[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(N1CCCN(C2CCCC2)CC1)N1CC(O)C1
Reactant: CC(C)(O)c1ccc(F)cn1
Product: CC(C)(O)c1ccc(OC2CN(C(=O)N3CCCN(C4CCCC4)CC3)C2)cn1

Procedure:
In a similar fashion (Route 20, GP I), 1-[(4-cyclopentyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-ol (100 mg, 0.41 mmol) and 2-(5-fluoropyridin-2-yl)propan-2-ol (90 mg, 0.41 mmol) were used to give the title compound. Crude material (38 mg) after workup gave the title compound as colourless oil (19.3 mg) after purification by preparative HPLC.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]#[CH:6])[CH3:3].C(NC(C)C)(C)C.[C:14]([C:18]1[CH:23]=[CH:22][C:21](/[C:24](/[C:41]2[CH:46]=[CH:45][C:44](I)=[CH:43][CH:42]=2)=[CH:25]/[CH2:26][O:27][C:28]2[CH:39]=[CH:38][C:31]([O:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[C:30]([CH3:40])[CH:29]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:14]([C:18]1[CH:19]=[CH:20][C:21](/[C:24](/[C:41]2[CH:46]=[CH:45][C:44]([C:6]#[C:5][CH2:4][N:2]([CH3:3])[CH3:1])=[CH:43][CH:42]=2)=[CH:25]/[CH2:26][O:27][C:28]2[CH:39]=[CH:38][C:31]([O:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[C:30]([CH3:40])[CH:29]=2)=[CH:22][CH:23]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C(C)(C)C)cc2)cc1C
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN(C)C)cc2)c2ccc(C(C)(C)C)cc2)cc1C
Temperature: 25 °C

Procedure:
1-(N,N-Dimethylamino)prop-2-yne (0.131 mL, 1.23 mmol) and diisopropylamine (0.40 mL, 2.85 mmol) were added to a solution of the methyl (Z)-[4-[3-(4-tert-butylphenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (350 mg, 0.614 mmol; prepared as described in example 30) in tetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide (10 mg, 0.053 mmol) and bis(triphenylphosphine)palladium(II) dichloride (22 mg, 0.031 mmol) were added. The reaction mixture was stirred at ambient temperature over night, filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, dichloromethane/methanol 98:2) yielding methyl (Z)-[4-[3-(4-tert-butylphenyl)-3-[4-[3-(N,N-dimethylamino)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate as oil.