Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[C:13](=[O:43])[C:14](=[CH:17][C:18]3[N:19]=[CH:20][N:21](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:22]=3[CH3:23])[CH2:15][CH2:16][C:5]=12)[CH:2]=[CH2:3]>C(O)(=O)C.[Zn]>[CH2:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[C:13](=[O:43])[CH:14]([CH2:17][C:18]3[N:19]=[CH:20][NH:21][C:22]=3[CH3:23])[CH2:15][CH2:16][C:5]=12)[CH:2]=[CH2:3]
Reactant: C=CCc1c2n(c3ccccc13)C(=O)C(=Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Agent: [Zn]
Solvent: CC(=O)O
Product: C=CCc1c2n(c3ccccc13)C(=O)C(Cc1nc[nH]c1C)CC2
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 10-allyl-8,9-dihydro-7-[(5-methyl-1-trityl-1H-imidazol-4-yl)methylene]pyrido[1,2-a]indol-6(7H)-one and zinc powder (2.0 g) in acetic acid (30 ml) was stirred vigorously at 100° C. for 2 hours. Zinc powder (1.5 g) was added and the mixture was heated for further 1 hour. After being cooled to room temperature, the insoluble material was filtered and washed with acetic acid. After evaporation of the solvent, the residue was diluted with water and washed twice with toluene. The toluene layer was extracted with 0.5N hydrochloric acid. The combined aqueous layers were neutralized with aqueous sodium bicarbonate solution and extracted three times with chloroform. The chloroform layer was washed with water twice and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. Chromatography (silica gel, 5% methanol-chloroform) of the residue, followed by recrystallization from methanol-chloroform-hexane, gave 10-allyl-8,9-dihydro-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (0.63 g).
Reaction SMILES: [Si](OC1C=C(C=CC=1)C(NNC(=O)[C@H](NC1C=CC(C#N)=C(Cl)C=1C)[C@H](O[Si](C(C)(C)C)(C)C)C)=O)(C(C)(C)C)(C)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Si:62]([O:69][C@@H:70]([CH3:102])[C@@H:71]([NH:91][C:92]1[CH:99]=[CH:98][C:95]([C:96]#[N:97])=[C:94]([Cl:100])[C:93]=1[CH3:101])[C:72]1[O:73][C:74]([C:77]2[CH:82]=[CH:81][CH:80]=[C:79]([O:83][Si:84]([C:87]([CH3:90])([CH3:89])[CH3:88])([CH3:86])[CH3:85])[CH:78]=2)=[N:75][N:76]=1)([C:65]([CH3:68])([CH3:67])[CH3:66])([CH3:64])[CH3:63]>>[Si:62]([O:69][C@H:70]([CH3:102])[C@@H:71]([NH:91][C:92]1[CH:99]=[CH:98][C:95]([C:96]#[N:97])=[C:94]([Cl:100])[C:93]=1[CH3:101])[C:72]1[O:73][C:74]([C:77]2[CH:82]=[CH:81][CH:80]=[C:79]([O:83][Si:84]([C:87]([CH3:88])([CH3:89])[CH3:90])([CH3:85])[CH3:86])[CH:78]=2)=[N:75][N:76]=1)([C:65]([CH3:66])([CH3:67])[CH3:68])([CH3:63])[CH3:64]
Reactant: Cc1c(N[C@@H](c2nnc(-c3cccc(O[Si](C)(C)C(C)(C)C)c3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: Cc1c(N[C@@H](C(=O)NNC(=O)c2cccc(O[Si](C)(C)C(C)(C)C)c2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1c(N[C@@H](c2nnc(-c3cccc(O[Si](C)(C)C(C)(C)C)c3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl

Procedure:
3-(tert-butyldimethylsilyloxy)-N′-((2R,3R)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)benzohydrazide (intermediate 9b) (362 mg, 0.57 mmol) was cyclized with PS-PPh3 (3.0 mmol/g, 389 mg, 1.2 mmol), 12 (289 mg, 1.1 mmol), and TEA (0.65 mL, 4.7 mmol) as described for the preparation of intermediate 7c. After column chromatography (20% EtOAc/hexanes) the title compound was isolated as a white solid (229 mg, 65%). 1H NMR (500 MHz, CDCl3, δ in ppm) 7.56 (m, 1H), 7.44 (m, 1H), 7.33 (m, 2H), 6.98 (m, 1H), 6.62 (d, J=8.8 Hz, 1H), 5.13 (ad, J=9 Hz, 1H), 4.83 (m, 1H), 4.44 (m, 1H), 2.32 (s, 3H), 1.30 (d, J=6.4 Hz, 3H), 0.99 (s, 9H), 0.93 (s, 9H), 0.21 (s, 6H), 0.13 (s, 3H), 0.11 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([C:8]1[CH:9]=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[CH2:26][NH:27][CH2:28][CH3:29])[C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)([CH3:7])[CH3:6])[CH3:2].Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>>[CH2:1]([O:3][C:4](=[O:30])[C:5]([C:8]1[CH:9]=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][C:17]=2[CH2:26][N:27]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:28][CH3:29])[C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(C(C)(C)C(=O)OCC)ccc1OC
Reactant: O=C(Cl)OCc1ccccc1
Product: CCOC(=O)C(C)(C)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: 2-(2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-2-methyl-propionic acid ethyl ester and benzyl chloroformate.
Reaction SMILES: COC(=O)[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=1)[C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6].[Cl-].[Na+]>CS(C)=O.O>[CH:7]1([C:5](=[O:6])[CH2:4][C:13]2[CH:14]=[CH:15][C:16]([I:19])=[CH:17][CH:18]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COC(=O)C(C(=O)C1CCCCC1)c1ccc(I)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(Cc1ccc(I)cc1)C1CCCCC1
Temperature: 150 °C
Yield: 96.1 %

Procedure:
According to a modified literature procedure (Collins, I. et al J. Med. Chem. 2002, 45, 1887-1900) a solution of 5.06 g (13.1 mmol) of 3-cyclohexyl-2-(4-iodo-phenyl)-3-oxo-propionic acid methyl ester in 80 mL of dimethylsulfoxide (DMSO) was added a solution of 1.53 g (26.2 mmol) of sodium chloride (NaCl) in 5.8 mL of water (H2O), and the resulting mixture was heated at 150° C. for 3 h during which time a white solid formed. The reaction mixture was cooled to rt, poured into 500 mL of water, and extracted thoroughly with ethyl acetate. The combined organic extracts were washed with water (3 times), brine, dried over sodium sulfate and concentrated to give 4.13 g (96% yield) of desired 1-cyclohexyl-2-(4-iodo-phenyl)-ethanone as a yellow solid as indicated by 1H NMR (containing small traces of impurities). The product was used without any further purification in the next step.
Reaction SMILES: CN(C)C=O.[C:6]([O:10][C:11]1[CH:12]=[C:13]([C:17]2[C:18]3[CH2:31][CH2:30][NH:29][C:19]=3[N:20]=[C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:22]=2)[CH:14]=[CH:15][CH:16]=1)([CH3:9])([CH3:8])[CH3:7].[H-].[Na+].[S:34](Cl)([C:37]1[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=1)(=[O:36])=[O:35]>O>[C:6]([O:10][C:11]1[CH:12]=[C:13]([C:17]2[C:18]3[CH2:31][CH2:30][N:29]([S:34]([C:37]4[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=4)(=[O:36])=[O:35])[C:19]=3[N:20]=[C:21]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[N:22]=2)[CH:14]=[CH:15][CH:16]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)Oc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCc3c(-c4cccc(OC(C)(C)C)c4)nc(N4CCOCC4)nc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
To a dimethylformamide solution (1 ml) of 4-(3-t-butoxyphenyl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (11 mg), sodium hydride (60% mineral oil dispersion, 1.5 mg, 1.2 equivalents) was added with ice cooling, followed by stirring at room temperature for 30 minutes. With ice cooling, tosyl chloride (6.6 mg, 1.1 equivalents) was added, followed by stirring at room temperature for 10 hours. To the reaction mixture, water (5 ml) was added, followed by extraction with ethyl acetate (5 ml×2). The organic layer was washed with aqueous ammonium chloride solution and brine, followed by drying over sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative TLC (n-hexane/ethyl acetate=2/1), to obtain the desired compound as a colorless powder (11 mg, 70%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:3]=1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([OH:31])=[C:26](B(O)O)[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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]>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([OH:31])=[C:24]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)[CH:3]=2)[CH:23]=1
Reactant: OB(O)c1cc(Cl)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(Br)ccn2)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(-c3cc(Cl)ccc3O)ccn2)CC1
Temperature: 70 °C
Yield: 67.5 %

Procedure:
tert-Butyl 4-(4-bromopyridin-2-yl)piperazine-1-carboxylate (1.00 g, 2.66 mmol), 5-chloro-2-hydroxyphenylboronic acid (458 mg, 2.66 mmol) and sodium carbonate (1.13 g, 10.64 mmol) were combined and dissolved in a mixture of dioxane/water (14 mL/4 mL). The reaction mixture was degassed for 20 min with nitrogen and then tetrakistriphenylphosphinepalladium (0) (153 mg, 0.133 mmol) was added. The reaction mixture was heated at 70° C. for 18 hours and then partitioned between ethyl acetate (20 mL) and water (10 mL). The organic layer was separated, washed with brine (10 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified on silica gel by Biotage™ (10% to 60% ethyl acetate in heptane over 20 CV) to give the title compound (700 mg, 66%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18]/[CH:19]=[C:20](/[C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[CH:24][CH:23]=2)\[CH3:21])=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Na+]>>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18]/[CH:19]=[C:20](/[C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[CH:26][CH:27]=2)\[CH3:21])=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccccc3C)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccccc3C)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared by hydrolysis of (E)-(S)-ethyl 2-ethoxy-3-{4-[3-(2′-methyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionate (example 92) (918 mg, 2.0 mmol) with sodium hydroxide by a procedure analogous to that described in example 51, yielding (E)-(S)-2-ethoxy-3-{4-[3-(2′-methyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionic acid as a colourless gum, which contained 0.25 mol equivalents of ethyl acetate; 586 mg (64%).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C(N(CC)CC)C.[C:12]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)(=[O:14])[CH3:13].Cl>C1COCC1>[C:12]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH:4][CH2:1][CH2:2][CH3:3])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)(=[O:14])[CH3:13]
Reactant: CCCN
Reactant: CC(=O)N1CCC(Cc2ccc(S(=O)(=O)Cl)cc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCNS(=O)(=O)c1ccc(CC2CCN(C(C)=O)CC2)cc1
Yield: 71.5 %

Procedure:
1-Propylamine (0.586 ml, 7.13 mmol) and triethylamine (0.993 ml, 7.13 mmol) were added to a solution of 4-(1-acetylpiperidin-4-ylmethyl)benzenesulfonylchloride (1.5 g, 4.75 mmol) in THF (20 ml) and this mixture was refluxed for 5 h. After having been cooled, 1N hydrochloric acid (20 ml) was added. The resulting mixture was extracted with ethyl acetate (20 ml×2). The combined organic layers were washed with saturated sodium chloride solution (40 ml), and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (silica gel 25 g, ethyl acetate to ethyl acetate/methanol=10/1) to give the title compound (1.15 g, 71%) as pale yellow oil.
Reaction SMILES: O1CCCC1.C([O:8][C:9](=O)[C@H:10]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=O)C.O>C(OCC)(=O)C>[C:26]([O:25][C:23]([N:22]1[C@@H:10]([CH2:9][OH:8])[CH2:11][CH2:12][C@H:13]1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CCOC(=O)[C@@H](CCC(=O)c1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](CO)CC[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 13 h
Yield: 104.4 %

Procedure:
Ice-cold lithium borohydride (277 mg) was added to a tetrahydrofuran (40 mL) solution of (2R,5S)-5-(4-chlorophenyl)pyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-ethyl ester (3 g) obtained in Example 8. Stirring was continued for 30 minutes at the same temperature and for 13 hours at room temperature. Water and ethyl acetate were added, and the organic layer was partitioned. The organic layer was washed with brine and was dried over anhydrous magnesium sulfate. The solvent was removed under a vacuum, and the title compound (2.64 g) was obtained. The physical property values are as follows.
Reaction SMILES: [CH:1]1([C:6]2[NH:11][C:10](=[O:12])[C:9]([CH:13]([NH:16][C:17](=O)[CH:18]([CH2:23][CH3:24])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH3:15])=[N:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O>>[CH:1]1([C:6]2[NH:11][C:10](=[O:12])[C:9]3=[C:13]([CH2:14][CH3:15])[N:16]=[C:17]([CH:18]([CH2:23][CH3:24])[CH2:19][CH2:20][CH2:21][CH3:22])[N:8]3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCCC(CC)C(=O)NC(CC)c1nnc(C2CCCC2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCC(CC)c1nc(CC)c2c(=O)[nH]c(C3CCCC3)nn12

Procedure:
In analogy to the procedure for Example 1, 190 mg (0.55 mmol) crude N-[1-(3-cyclopentyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]-2-ethylhexanamide, 165 mg (1.1 mmol) phosphoric trichloride are stirred at reflux for 4 hours, proportionate amounts of the solvents are used. The product is purified by chromatography (preparative HPLC).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14].CO>C(Cl)Cl>[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:14])=[O:15]
Reactant: COc1ccccc1S(N)(=O)=O
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: NS(=O)(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
22.2 ml of boron tribromide are added dropwise, under nitrogen and at room temperature, over 15 minutes to a suspension of 39 g of 2-methoxyphenylsulfonamide in 210 ml of dry methylene chloride. The reaction mixture is then stirred for 1 hour at room temperature. After the mixture has been cooled to 0° C., 200 ml of methanol are added over 15 minutes and the clear solution is concentrated. The oily residue is taken up in ethyl acetate and the solution is washed twice with water, dried over sodium sulfate, and evaporated to dryness. The residue is triturated with petroleum ether, affording 25.1 g of 2-hydroxyphenylsulfonamide with a melting point of 136°-138° C.
Reaction SMILES: [C:1]([NH:8][N:9]1[C:15](=[O:16])[CH2:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]1=2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:32][CH:33]([CH3:35])[CH3:34]>CN(C=O)C.C(Cl)Cl>[C:1]([NH:8][N:9]1[C:15](=[O:16])[CH:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]1=2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)CI
Reactant: CC(C)(C)OC(=O)NN1C(=O)Cc2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)CC1C(=O)N(NC(=O)OC(C)(C)C)c2ccccc2-c2ccccc21
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A solution of 5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (0.2 g, 0.617 mmol) (Example 7-E) in DMF was treated with Cs2CO3 (0.22 g, 0.678 mmol) and warmed to 60° C. To the reaction mixture was added 1-iodo-2-methylpropane (0.078 ml, 0.678 mmol) and stirring continued for 17 h. After cooling to 23° C. the mixture was diluted with CH2Cl2, washed with several portions of brine and dried over Na2SO4. The title compound was purified by chromatography (SiO2, CHCl3/MeOH 9:1).
Reaction SMILES: [CH3:1][C:2](O)([CH3:4])[CH3:3].[C:6]([O:10][C:11]([NH:13][CH:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH3:27])[CH:20]=1)[C:15]([OH:17])=[O:16])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[C:6]([O:10][C:11]([NH:13][CH:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH3:27])[CH:20]=1)[C:15]([O:17][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:16])=[O:12])([CH3:8])([CH3:9])[CH3:7]
Reactant: COc1cc(CC(NC(=O)OC(C)(C)C)C(=O)O)ccc1O
Reactant: CC(C)(C)O
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(CC(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc1O
Temperature: 25 °C

Procedure:
t-BuOH (5.17 g, 6.67 mL, 69.8 mmol) was added to a stirred suspension of 2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxy-3-methoxyphenyl)propanoic acid (1.55 g, 4.98 mmol) in dry toluene (25 mL). The mixture was brought to reflux to give a homogeneous solution. N,N-dimethylformamide dineopentyl acetal (3.46 g, 4.17 mL, 15.0 mmol) was added dropwise over 1 h at reflux. After heating at reflux to 3-4 h, the reaction mixture was cooled to room temperature and a saturated solution of NaHCO3 (40 mL) was added. The mixture was extracted with CH2Cl2 (3×40 mL) and the combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Biotage Horizon, 40M, Si, ˜30 mL/min, 100% hexanes for 360 mL, gradient to 20% EtOAc in hexanes over 4536 mL) to afford tert-butyl 2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxy-3-methoxyphenyl)propanoate. Rf=0.42 (20% EtOAc/hexanes). LCMS calc.=390.2; found=389.9 (M+Na)+. 1H NMR (500 MHz, CDCl3): δ 6.82 (d, J=7.9 Hz, 1 H); 6.87-6.63 (m, 2 H); 5.54 (s, 1 H); 4.97 (d, J=7.8 Hz, 1 H); 4.40 (q, J=6.7 Hz, 1 H); 3.86 (s, 3 H); 2.98 (d, J=6.0 Hz, 2 H); 1.42 (s, 9 H); 1.41 (s, 9 H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH2:17][C:18]([C:20]2[CH:21]=[CH:22][C:23]3[C:32]4[CH:31]=[C:30]5[CH2:33][CH2:34][CH:35](Br)[C:36](=[O:37])[C:29]5=[CH:28][C:27]=4[O:26][CH2:25][C:24]=3[CH:39]=2)=[O:19])=[O:15])[CH2:3]1.[C:40]([O:44][C:45]([N:47]1[CH2:51][C@@H:50]([CH2:52][O:53][CH3:54])[CH2:49][C@H:48]1[C:55]([OH:57])=[O:56])=[O:46])([CH3:43])([CH3:42])[CH3:41].C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl>[CH3:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH2:17][C:18]([C:20]2[CH:21]=[CH:22][C:23]3[C:32]4[CH:31]=[C:30]5[CH2:33][CH2:34][CH:35]([O:57][C:55]([C@@H:48]6[CH2:49][C@H:50]([CH2:52][O:53][CH3:54])[CH2:51][N:47]6[C:45]([O:44][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:46])=[O:56])[C:36](=[O:37])[C:29]5=[CH:28][C:27]=4[O:26][CH2:25][C:24]=3[CH:39]=2)=[O:19])=[O:15])[CH2:3]1
Reactant: C[C@H]1C[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCC(Br)C4=O)N(C(=O)OC(C)(C)C)C1
Reactant: COC[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: COC[C@H]1C[C@@H](C(=O)OC2CCc3cc4c(cc3C2=O)OCc2cc(C(=O)COC(=O)[C@@H]3C[C@H](C)CN3C(=O)OC(C)(C)C)ccc2-4)N(C(=O)OC(C)(C)C)C1
Temperature: 50 °C
Yield: 71 %

Procedure:
(2S,4S)-2-(2-(9-bromo-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl) 1-tert-butyl 4-methylpyrrolidine-1,2-dicarboxylate (709 mg, 1.18 mmol) was treated with a solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylic acid (614 mg, 2.36 mmol) in Me-THF (12 mL) and Cs2CO3 (384 mg, 1.18 mmol). The stirred reaction mixture was heated to 50° C. for 16 h, then cooled to RT and diluted with CH2Cl2 and extracted 3×. The organic phase was washed with brine, then dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (40% to 100% EtOAc/hexanes) to afford (2S,4S)-2-(2-(9-((2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carbonyloxy)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl) 1-tert-butyl 4-methylpyrrolidine-1,2-dicarboxylate (651 mg, 71%).
Reaction SMILES: [CH3:1][C@H:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:3][CH:4]=O.[CH3:12][C:13]([CH3:15])=[O:14]>O>[CH3:1][C@H:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:3]/[CH:4]=[CH:12]/[C:13](=[O:14])[CH3:15]
Reactant: CC(C)=O
Reactant: CC(C)=CCC[C@@H](C)CC=O
Solvent: O
Product: CC(=O)/C=C/C[C@H](C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 4.25 h

Procedure:
To a solution of 25 g (R)-3,7-dimethyl-6-octenal [(R)-citronellal] (chemical purity according to gas chromatography 98.3-98.5%; enantiomeric purity 97-97.6% ee) in 70 ml acetone and 170 ml of water there was added 9.8 g of barium hydroxyde-octahydrate and the mixture was stirred under argon a 68°-69° C. during 4.25 hours. Thereafter, the reaction mixture was cooled to room temperature and extracted two times with 500 ml of n-hexane. The organic phases were combined, washed with 100 ml of water and with 50 ml of 5% aqueous acetic acid, dried over sodium sulfate and concentrated. The so obtained (3E,6R)-6,10-dimethyl-3,9-undecadiene-2-one was 92% chemically pure according to gas chromatography.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([F:19])[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:9]2)([O-])=O.Br[CH2:21][C:22]([O:24][CH3:25])=[O:23]>>[CH3:25][O:24][C:22](=[O:23])[CH2:21][NH:1][C:4]1[CH:5]=[C:6]([F:19])[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:9]2
Reactant: O=[N+]([O-])c1cc(F)cc2cc(-c3ccccc3)[nH]c12
Reactant: COC(=O)CBr
Product: COC(=O)CNc1cc(F)cc2cc(-c3ccccc3)[nH]c12

Procedure:
7-Nitro-5-fluoro-2-phenyl-1H-indole prepared in Preparation 27 and methyl bromoacetate were reacted according to the same procedures as Step A of Example 1 and Example 22 sequentially to give the title compound.
Reaction SMILES: [BH4-].[Na+].CO.[F:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH3:28])[C:13]2[N:18]=[C:17]3[S:19][C:20]([NH:22][C:23]([CH:25]4[CH2:27][CH2:26]4)=[O:24])=[N:21][C:16]3=[CH:15][CH:14]=2)=[CH:8][C:7]=1[NH:29]C(=O)C(F)(F)F.[Cl-].[NH4+]>C(O)C.C(OCC)(=O)C>[NH2:29][C:7]1[CH:8]=[C:9]([N:12]([CH3:28])[C:13]2[N:18]=[C:17]3[S:19][C:20]([NH:22][C:23]([CH:25]4[CH2:26][CH2:27]4)=[O:24])=[N:21][C:16]3=[CH:15][CH:14]=2)[CH:10]=[CH:11][C:6]=1[F:5]
Reactant: CN(c1ccc(F)c(NC(=O)C(F)(F)F)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(c1ccc(F)c(N)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
To a suspension of sodium borohydride (3.34 g, 88.2 mmol) in ethanol (40 mL) were added methanol (1 mL) and N-[5-[{4-fluoro-3-[(trifluoroacetyl)amino]phenyl}(methyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (1.71 g, 3.77 mmol) at 4° C., and the mixture was stirred for 30 min. The reaction mixture was poured into a two-layer solvent of ethyl acetate (200 mL) and 5% aqueous ammonium chloride solution (200 mL), and the mixture was vigorously stirred at room temperature for 5 min. The aqueous layer was separated, and extracted with ethyl acetate (200 mL). The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (200 mL) and saturated brine (200 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→60/40), and the obtained solution was concentrated under reduced pressure to give the title compound (1.19 g, 88%) as a colorless powder.