Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4]([C:13]([OH:15])=O)=[C:3]1[CH3:16].C(Cl)(=O)C(Cl)=O.[CH2:23]([NH2:27])[CH:24]([CH3:26])[CH3:25]>>[CH2:23]([NH:27][C:13]([C:4]1[C:5]2[C:10](=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[N:2]([CH3:1])[C:3]=1[CH3:16])=[O:15])[CH:24]([CH3:26])[CH3:25]
Reactant: COc1ccc2c(C(=O)O)c(C)n(C)c2c1
Reactant: CC(C)CN
Agent: O=C(Cl)C(=O)Cl
Product: COc1ccc2c(C(=O)NCC(C)C)c(C)n(C)c2c1

Procedure:
This material was prepared from 1,2-dimethyl-6-methoxy-1H-indole-3-carboxylic acid 16c, oxalyl chloride and isobutylamine in a manner as previously described for example 16d. 1H NMR (300 MHz, CDCl3) δ 7.56 (1H, d, J=8.6 Hz), 6.85 (1H, dd, J=2.2, 8.6 Hz), 6.78 (1H, d, J=2.2 Hz), 3.87 (3H, s), 3.63 (3H, s), 3.32 (2H, m), 2.69 (3H, s), 1.93 (1H, m), 1.02 (3H, s), 1.00 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 275. found 275.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[N:19]1([CH2:24][CH2:25][CH2:26][NH2:27])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:27][CH2:26][CH2:25][CH2:24][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: NCCCN1CCCC1
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NCCCN1CCCC1

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (266 mg, 1.0 mmol) was treated with 3-pyrrolidin-1-yl-propylamine following general procedure B to afford 8-methoxy-4-(3-pyrrolidin-1-yl-propylamino)-quinoline-3-carboxylic acid ethyl ester (315 mg). Thus obtained amino-ester (36 mg, 0.1 mmol) was subjected to reaction with ethyl isocyanate according to general procedure C to furnish 3-ethyl-7-methoxy-1-(3-pyrrolidin-1-yl-propyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (19 mg). LCMS: m/z 383 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][OH:14].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][O:14][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCc1c[nH]c2ccc(F)cc12
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCc2c[nH]c3ccc(F)cc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
To a stirred solution of 3-(5-fluoro-1H-indol-3-yl)-propan-1-ol (2.90 g, 15.0 mmol) in pyridine (15.0 mL) was added p-toluenesulfonyl chloride (7.1 g, 37.5 mmol) at room temperature. After stirring for 30 minutes at room temperature, the reaction mixture was poured to 200 mL of ice water. The aqueous was extracted with ethyl acetate and the combined organic extracts were washed with 1N HCl and brine. The resulting material was dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under vacuum. The crude product was purified by silica gel column chromatography (ethyl acetate/hexane, 3/7) to give 4.1 g (79%) of the title compound as a solid: mp 74° C. (Lit. mp 99° C.; EP 464604 A2).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[N:6](C=[N+](CC(=O)C3C=CC=CC=3)[N:10]=2)[N:7]=1.[OH-].[Na+]>>[CH3:20][C:4]1[CH:3]=[C:2]([CH3:1])[N:7]=[N:6][C:5]=1[NH2:10]
Reactant: Cc1cc(C)c2n[n+](CC(=O)c3ccccc3)cn2n1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C)c(N)nn1
Yield: 92.6 %

Procedure:
A solution of alkylated salt 2 (2.58 g, 9.65 mmol) in 20% aqueous NaOH solution (29.0 mmol) was heated at reflux for 16 h. The crude reaction mixture was evaporated to dryness and purified by silica gel column chromatography (CHCl3/MeOH, 10:1 (v/v), as eluent), to yield 3 (1.1 g, 93%) as a pale, brown powder; mp: 123-126° C. 1H NMR (CDCl3, 300 MHz) δ: 2.13 (s, 3H), 2.50 (s, 3H), 6.93 (s, 1H). Mass Spectrum: CI, m/z 124 (M+1).
Reaction SMILES: C([O:5][C:6](=[O:46])[CH2:7][N:8](C(OC(C)(C)C)=O)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[N:10]=1)(C)(C)C.C(OC(=O)CN(C(OC(C)(C)C)=O)C1C=CC=C(C(CC2C=CC(N3C=CC=N3)=CC=2)NS(C2C=CC=CN=2)(=O)=O)N=1)(C)(C)C>>[F:38][C:35]1[CH:36]=[CH:37][C:32]([S:29]([CH:15]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[C:11]2[N:10]=[C:9]([NH:8][CH2:7][C:6]([OH:46])=[O:5])[CH:14]=[CH:13][CH:12]=2)(=[O:30])=[O:31])=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(NCc2ccc(-n3cccn3)cc2)S(=O)(=O)c2ccc(F)cc2)n1
Agent: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(Cc2ccc(-n3cccn3)cc2)NS(=O)(=O)c2ccccn2)n1
Product: O=C(O)CNc1cccc(C(NCc2ccc(-n3cccn3)cc2)S(=O)(=O)c2ccc(F)cc2)n1
Yield: 85.5 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Example 21-(b) except for using tert-butyl[tert-butoxycarbonyl(6-{(4-fluorobenzenesulfonyl)[4-(pyrazol-1-yl)benzyl]aminomethyl}pyridin-2-yl)amino]acetate (794 mg, 1.22 mmol) obtained in Example 26-(a) in place of tert-butyl[tert-butoxycarbonyl(6-{[4-(pyrazol-1-yl)benzyl](pyridin-2-ylsulfonyl)aminomethyl}pyridin-2-yl)amino]-acetate to afford the title compound (517 mg) as a white solid. (Yield: 86%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[CH:17][C:16]=3[OH:23])[CH2:10][CH2:9]2)[C:3]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1.C(OC([N:38]1[CH2:41][CH:40](I)[CH2:39]1)=O)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[NH:38]1[CH2:41][CH:40]([O:23][C:16]2[CH:17]=[C:18]([Cl:22])[C:19]([Cl:21])=[CH:20][C:15]=2[CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=3[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:9][CH2:10]2)[CH2:39]1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: Nc1ncnc(N2CCN(Cc3cc(Cl)c(Cl)cc3O)CC2)c1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnc(N2CCN(Cc3cc(Cl)c(Cl)cc3OC3CNC3)CC2)c1-c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
A reaction mixture of 2-{4-[6-amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-ylmethyl}-4,5-dichloro-phenol (80.0 mg; 0.18 mmol; 1.00 eq.), 3-iodo-azetidine-1-carboxylic acid tert-butyl ester (60.6 mg; 0.21 mmol; 1.20 eq.) and cesium carbonate (116.2 mg; 0.36 mmol; 2.00 eq.) in DMF (1 ml) was stirred at 90° C. overnight. The reaction solution was poured to water and extracted with ethyl acetate, The separated organic layer was washed with brine, dried and concentrated, which was then dissolved in methanol (1 ml) followed by adding 4.0 M HCl in dioxane (2 ml) and stirred at RT overnight. The reaction mixture was concentrated and purified by Waters prep-HPLC (acidic condition) to yield the title compounds (37 mg, yield 33.6%). LC-MS: (M+1=504, obsd.=504/506).
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH3:6][O:7][N:8]([CH3:35])[C:9]([C:11]1[S:12][C:13]([C:17]2[CH:18]=[C:19]([C:25]3[CH:30]=[CH:29][C:28]([S:31](=[O:34])(=[O:33])[NH2:32])=[CH:27][CH:26]=3)[C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[C:14]([CH3:16])[N:15]=1)=[O:10]>C(OCC)(=O)C>[CH3:1][N:2]([CH:4]=[N:32][S:31]([C:28]1[CH:29]=[CH:30][C:25]([C:19]2[C:20]([O:23][CH3:24])=[CH:21][CH:22]=[C:17]([C:13]3[S:12][C:11]([C:9]([N:8]([O:7][CH3:6])[CH3:35])=[O:10])=[N:15][C:14]=3[CH3:16])[CH:18]=2)=[CH:26][CH:27]=1)(=[O:34])=[O:33])[CH3:3]
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2sc(C(=O)N(C)OC)nc2C)cc1-c1ccc(S(N)(=O)=O)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2sc(C(=O)N(C)OC)nc2C)cc1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.33 %

Procedure:
DMF (0.7 ml) and DMF acetal (0.22 g, 0.25 ml, 1.88 mmol) were added subsequently to a solution of N-methoxy-5-(6-methoxy-4′-sulfamoyl-[1,1′-biphenyl]-3-yl)-N,4-dimethylthiazole-2-carboxamide (8c, 0.70 g, 1.56 mmol) in ethyl acetate (12 ml) at room temperature. The reaction mixture was then stirred at room temperature for 15 hr under nitrogen atmosphere. The progress of the reaction was monitored by TLC. The solid obtained was filtered and washed with ether (10 ml) to obtain the title compound 8d (0.60 g, 76.33%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][C@@H:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[NH2:21])=[CH:17][CH:16]=1.ClCl>C(=O)([O-])[O-].[K+].[K+]>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:21][C@H:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:19][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:28][CH:27]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Agent: ClCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)[C@H](Cc1ccc(OC)cc1)NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Yield: 92.4 %

Procedure:
5 g of 3,4-dichlorophenylsulphonyl chloride are introduced, with stirring, into a mixture of 3,8 g of ethyl O-methyltyrosinate in 35 ml of CH2 Cl2 and 50 ml of a saturated aqueous potassium carbonate solution. After one night, the solid is removed, the organic phase separated and the aqueous phase reextracted with CH2Cl2. The dried organic phases are concentrated and the residue is chromatographed on a silica column, eluting with a mixture of CH2Cl2 and CH3OH (95/5-V/V). 6.8 g of racemic ethyl N-(3,4-dichlorophenylsulphonyl)-O-methyltyrosinate are obtained, which product melts at 99° C. This ester is hydrolysed in 100 ml of C2H5OH containing 9.5 ml of a 5N aqueous KOH solution to give, after acidification, 5.5 g of the corresponding acid which melts at 183° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[Cl:15][C:16]1[CH:21]=[C:20]([O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([S:29][CH3:30])[N:24]=2)[CH:19]=[CH:18][C:17]=1[NH2:31]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:31][C:17]2[CH:18]=[CH:19][C:20]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([S:29][CH3:30])[N:24]=3)=[CH:21][C:16]=2[Cl:15])=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: CSc1nccc(Oc2ccc(N)c(Cl)c2)n1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1CCOC1
Product: CSc1nccc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c(Cl)c2)n1
Reaction time: 8 h
Yield: 26.1 %

Procedure:
A solution of 281 mg (1.27 mmol) 4-chloro-3-trifluoromethyl-phenyl isocyanate in 3 ml THF was added within 5 min. drop by drop at 0° C. to a solution of 340 mg (1.27 mmol) 2-chloro-4-(2-methylsulfanyl-pyrimidin-4-yloxy)-phenylamine and stirring continued at r.t. overnight. The reaction mixture was evaporated and purified by chromatography on silica (ethyl acetate/isohexane 1:4) to give 162 mg (26%) 1-(4-chloro-3-trifluoromethyl-phenyl)-3-[2-chloro-4-(2-methylsulfanyl-pyrimidin-4-yloxy)-phenyl]-urea.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:10][C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][C:13]1[CH:17]=[C:16]([CH3:18])[NH:15][C:14]=1[CH:19]=O>>[Cl:1][C:2]1[C:3]2[C:10](=[CH:19][C:14]3[NH:15][C:16]([CH3:18])=[CH:17][C:13]=3[CH3:12])[C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Reactant: Cc1cc(C)c(C=O)[nH]1
Product: Cc1cc(C)c(C=C2C(=O)Nc3ncnc(Cl)c32)[nH]1
Yield: 44.5 %

Procedure:
4-Chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (1 eq.) was condensed with 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (1 eq.) at room temperature to give (44.5%) of 4-chloro-5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]=[CH:8][C:9](=[O:17])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1.C(O)C.[H][H]>[Ni].O>[CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][C:9](=[O:17])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CCOC(=O)CCC(=O)C=Cc1ccc(C)o1
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCC(=O)CCc1ccc(C)o1
Temperature: 70 °C

Procedure:
For the hydrogenation reaction, 10 g of ethyl 6-(5-methylfuran-2-yl)-4-oxohex-5-enoate, 1 g of 10% wet weight basis Raney Nickel, 100 mL of ethanol, and 5 mL of water were combined in a Parr Bottle. The mixture was pressurized to 50 psi with hydrogen gas and heated to 70° C. The mixture was stirred until hydrogen uptake stopped. The mixture was cooled to ambient temperature, filtered, and washed with ethanol. The filtrate was rotary evaporated to yield ethyl 6-(5-methylfuran-2-yl)-4-oxohexanoate. The ethyl 6-(5-methylfuran-2-yl)-4-oxohexanoate (9.9 g) was then dissolved in hexanes solvent (Aldrich) and dried with sodium sulfate. The solids were filtered, and washed with hexanes. The hexane was combined with the liquid extract and evaporated to an oil. The oil was dissolved in 100 mL isopropyl alcohol (IPA) and added to a Parr bottle containing IPA-washed Raney Nickel (5.0 g wet weight). The reaction mixture was pressurized to 50 psi with hydrogen gas and heated to 70° C. The reaction mixture was stirred until hydrogen uptake stopped. The Raney Nickel was filtered off and washed with IPA. The IPA was then combined with the liquid extract and evaporated to produce ethyl 4-hydroxy-6-(5-methyltetrahydrofuran-2-yl)hexanoate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([C:32]([CH:29]2[CH2:31][CH2:30]2)=[O:33])[CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Cl)C1CC1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and cyclopropanecarbonyl chloride.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CN(C=O)C>[CH3:11][O:10][C:9]1[C:2]([O:1][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH:4]=[O:5]
Reactant: COc1cccc(C=O)c1O
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOc1c(C=O)cccc1OC
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2-Hydroxy-3-methoxybenzaldehyde (3.00 g, 19.7 mmol) and DMF (25 ml) were mixed, and potassium carbonate (3.00 g, 22.0 mmol) and bromopentane (2.73 ml, 22.0 mmol) were successively added to this solution. The reaction mixture was stirred at 100° C. for 2 hours and the obtained solid was filtered. Water (20 ml) and ethyl acetate (50 ml) were added for separation. The aqueous layer was extracted twice with ethyl acetate (25 ml). The organic layers were combined, washed twice with saturated brine (20 ml) and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product of 3-methoxy-2-pentyloxybenzaldehyde. (2) THF (30 ml) and methyl (triphenylphosphoranilidene)acetate (7.36 g, 22.0 mmol) were added to the above-mentioned compound. The mixture was re iuxed under heating for 5.5 hours and THF was evaporated under reduced pressure. Hexane (100 ml) was added to the obtained residue, and the precipitated crystals were filtered off. The filtrate was concentrated under reduced pressure. To the obtained residue were added ethanol (40 ml) and a 1N aqueous sodium hydroxide solution (40 ml). The mixture was refluxed under heating for 1 hour. After removing ethanol by evaporation under reduced pressure, concentrated hydrochloric acid was added to make the aqueous layer acidic. The aqueous layer was extracted twice with ethyl acetate (70 ml). The organic layers were combined, washed 3 times with saturated brine (40 ml) and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained crude crystals were recrystallized from ethyl acetate to give 3- (3-methoxy-2-pentyloxyphenyl)cinnamic acid (3.82 g, 73% in 3 steps) as colorless needles.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([NH:15][C:16](=[O:28])[C@@H:17]([N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>CO.O1CCCC1.[C].[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([NH:15][C:16](=[O:28])[C@@H:17]([N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH3:18])[CH:12]=[CH:13][CH:14]=1
Reactant: C[C@@H](C(=O)Nc1cccc(OCc2ccccc2)c1)N(C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](C(=O)Nc1cccc(O)c1)N(C)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 107 %

Procedure:
To 10% palladium-carbon (100 mg), a solution of (S)-tert-butyl (1-((3-(benzyloxy)phenyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (E15, 166 mg) in methanol (4 mL) and tetrahydrofuran (2 mL) was added at room temperature, and the mixture was stirred at the same temperature for 5 hours and 30 minutes under a hydrogen atmosphere. The insoluble matter was removed by filtration through Cerite, and then the solvent was evaporated under reduced pressure to obtain (S)-tert-butyl (1-((3-hydroxyphenyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (E16, 136 mg).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+:10].[C:11]1([CH3:20])[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[S:19])=[CH:13][CH:12]=1.[CH3:21][CH2:22][OH:23]>C1COCC1.C(#N)C>[C:14]([C:13]1[CH:12]=[CH:21][C:22](=[O:23])[N:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:20])=[CH:12][CH:13]=2)[C:18]=1[S-:19])#[N:17].[Na+:10]
Reactant: Cc1ccc(N=C=S)cc1
Reactant: CCO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1ccc(-n2c([S-])c(C#N)ccc2=O)cc1
Temperature: 25 °C
Yield: 39 %

Procedure:
Sodium bis(trimethylsilyl)amide (36.8 mL, 1.0M in THF, 36.8 mmol) was added slowly to a solution of 4-tolyl isothiocyanate (2.5 g, 16.75 mmol) in THF (30 mL) and acetonitrile (5 mL) at −78° C. The mixture was warmed to r.t. over 1 h. N,N-Dimethyluracil (2.35 g, 16.75 mmol) and EtOH (20 mL) were added and the mixture heated at reflux for 4 h. Volatiles were removed in vacuo and the residue was dissolved in EtOH (6 mL). Et2O (˜60 mL) was added slowly to produce a fine, off-white solid. The suspension was cooled to 0° C. and the solid filtered off, washed with Et2O and dried to give the title compound as an off-white solid (1.7 g, 39%). δH (DMSO-d6) 7.15-7.12 (3H, m), 6.80-6.77 (2H, m), 5.60 (1H, d, J 9.1 Hz), 2.30 (3H, s).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:11][C:12]1[N:17]=[CH:16][C:15]([CH2:18][C:19]#[N:20])=[CH:14][CH:13]=1.I[CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>C1COCC1.C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[Cl:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:19]#[N:20])=[CH:14][CH:13]=1
Reactant: N#CCc1ccc(Cl)nc1
Reactant: ICC1CCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#CC(CC1CCCC1)c1ccc(Cl)nc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
KHMDS (30.9 mL of a 1 mmol mL−1 solution in THF, 30.9 mmol) was added to a stirred solution of (6-chloropyridin-3-yl)acetonitrile (4.40 g, 28.9 mmol) in anhydrous THF-HMPA (3:1, 72 mL) at −78° C. After 30 min, iodomethylcyclopentane (1.46 g, 6.9 mmol) was added. The solution was stirred at −78° C. for 4.5 h, before being allowed to warm to 20° C. over 16 h. The reaction mixture was carefully quenched with saturated aqueous NH4Cl (20 mL), then H2O (100 mL) was added. The mixture was extracted with EtOAc (3×50 mL), then the extracts were dried (Na2SO4). Filtration, solvent evaporation, and column chromatography (n-C6H14-EtOAc) furnished 2-(6-chloropyridin-3-yl)-3-cyclopentylpropionitrile: m/z (ES+)=235.1 [M+H]+. Step 2: This compound (2.30 g, 9.8 mmol) was heated with 50% aqueous H2SO4 (10 mL) at 130° C. for 2 h with stirring. The mixture was allowed to cool down to 20° C. over 16 h, before being neutralised with saturated aqueous Na2CO3 and extracted with CHCl3. The organic extracts were dried (Na2SO4), before being filtered and concentrated to give the title compound: m/z (ES+)=254.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH:5]([CH3:7])[CH3:6])[CH:3]=[CH2:4].C1C[O:12]CC1>>[CH3:1][C:2]([CH3:8])([CH:5]([CH3:7])[CH3:6])[CH2:3][CH2:4][OH:12]
Reactant: C1CCOC1
Reactant: C=CC(C)(C)C(C)C
Product: CC(C)C(C)(C)CCO
Temperature: 25 °C

Procedure:
3,3,4-Trimethylpentene (1 equiv) is dissolved in dry THF under Ar. The reaction mixture is cooled to −78° C. at which time a 1 M solution of borane/dimethylsulfide complex in THF (0.4 equiv) is added dropwise. The cold bath is removed and the reaction mixture is allowed to warm to ambient temperature. The reaction mixture is carefully diluted with a solution of sodium acetate in aqueous hydrogen peroxide (large exess). The reaction mixture is stirred at ambient temperature and then diluted with diethyl ether and the layers are separated. The organic layer is dried over Na2SO4, decanted and concentrated. The crude material is purified by fractional distillation to yield 3,3,4-trimethylpentanol.
Reaction SMILES: [CH2:1]([C:4]1[C:16]([O:17][CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[CH:15][CH:14]=[C:13]2[C:5]=1[C:6]1[CH2:7][CH2:8][CH2:9][CH:10]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:11]=1[NH:12]2)[CH:2]=[CH2:3].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C1(C)C=CC=CC=1.[Cl:52][C:53]1[CH:60]=[CH:59][C:56]([CH2:57]Br)=[CH:55][CH:54]=1.[NH4+].[Cl-]>C1COCC1.CN(C)P(N(C)C)(N(C)C)=O>[Cl:52][C:53]1[CH:60]=[CH:59][C:56]([CH2:57][N:12]2[C:11]3[CH:10]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:9][CH2:8][CH2:7][C:6]=3[C:5]3[C:13]2=[CH:14][CH:15]=[C:16]([O:17][CH2:18][C:19]2[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=2)[C:4]=3[CH2:1][CH:2]=[CH2:3])=[CH:55][CH:54]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: C=CCc1c(OCc2ccc3ccccc3n2)ccc2[nH]c3c(c12)CCCC3CC(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CCc1c(OCc2ccc3ccccc3n2)ccc2c1c1c(n2Cc2ccc(Cl)cc2)C(CC(=O)OCC)CCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 454 mg (1 mmol) of ester from Step 5 in THF (15 ml) at -78° C. is added lithium hexamethyldisilazide in toluene (1.1 mmol), followed by hexamethylphosphoramide (1.5 ml). After 15 minutes, p-chlorobenzyl bromide (300 mg) is added and the reaction is allowed to warm to room temperature. The reaction mixture is then poured into 5% aqueous NH4Cl, extracted with 2×100 ml Et2O and the organic extracts dried over MgSO4. Filtration and evaporation of the solvent left a crude residue, which, after chromatography over silica using EtOAc-hexane, yields ethyl 9-p-chlorobenzyl-6-(quinolin-2-ylmethoxy)-5-allyl-1,2,3,4-tetrahydrocarbazol-1-ylacetate.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[O:17]([C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: Oc1ccccc1
Product: O=[N+]([O-])c1cccc(Oc2ccccc2)c1

Procedure:
The compound above was prepared from 3-iodonitrobenzene (925 mg) and phenol, using the procedure described in Example 5 Step 1. The crude product was used without further purification.