Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4](S(C2C=CC=CC=2)(=O)=O)[C:3]=1[CH2:20][CH2:21][NH:22][CH:23]([C:25]1[N:26]=[CH:27][N:28]([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29]=1[CH3:30])[CH3:24].[OH-].[K+]>CS(C)=O.O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[CH2:20][CH2:21][NH:22][CH:23]([C:25]1[N:26]=[CH:27][N:28]([C:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:29]=1[CH3:30])[CH3:24]
Reactant: Cc1c(CCNC(C)c2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C)n(S(=O)(=O)c2ccccc2)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(CCNC(C)c2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C)[nH]c2ccccc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
A mixture of 3-methyl-2-[2-[[1-(5-methyl-1-trityl-1H-imidazol-4-yl)ethyl]amino]ethyl]-1-phenylsulfonylindole (970 mg) and powdered potassium hydroxide (819 mg) in dimethylsulfoxide (10 ml) were stirred at 70° C. for 1 hour. The resultant mixture was diluted with cold water and extracted twice with 30% tetrahydrofuran in ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (eluted with 5% MeOH in chloroform) to give 3-methyl-2-[2-[[1-[5-methyl-1-trityl-1H-imidazol-4-yl)ethyl]amino]ethyl]indole (611.3 mg) as amorphous powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6])[CH3:2].[O-]S([O-])(=O)=O.[Mg+2].[CH:15](=O)[C:16]([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:8])[C@H:5]([CH3:7])[N:6]=[CH:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:2]
Reactant: CC(C)(C)C=O
Reactant: CCOC(=O)[C@H](C)N
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)N=CC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Step-2. L-Alanine ethyl ester from step-1 (9 g) was dissolved in 150 ml anhydrous CH2Cl2. The solution was cooled to 0° C. MgSO4 (10.17 g) was added to the solution followed by addition of pivalaldehyde (6.95 g). The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was filtered and the filtrate was evaporated to give 11.2 g of N-neopentylidene-L-alanine ethyl ester. The product was used for next step without further purification. MS: 186 (MH+).
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]3[CH2:26][CH2:25][C:20]4(OCC[O:21]4)[CH2:19][CH2:18]3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[N:1]1([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]3[CH2:18][CH2:19][C:20](=[O:21])[CH2:25][CH2:26]3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2c(c1)nnn2-c1ccnc(NC2CCC3(CC2)OCCO3)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCC(Nc2nccc(-n3nnc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70 %

Procedure:
To a suspension of (4-benzotriazol-1-yl-pyrimidin-2-yl)-(1,4-dioxa-spiro[4.5]dec-8-yl)-amine (prepared in a similar manner as described in Example 2) (1.53 g, 4 mmol) in 80 mL of THF was added 25 mL of a 3 M aqueous solution of HCl. The reaction mixture was stirred at RT for 20 minutes. The reaction was heated to reflux for 30 minutes. It was then cooled, and poured onto an aqueous NaHCO3 solution. The resulting mixture was extracted with EtOAc, dried over Na2SO4 and filtered. The solvent was evaporated under reduced pressure until the product began to crystallize out of solution; it was then filtered and dried to give the title product as a white powder (942 mg, 70% yield); mp=204.9-206.5° C.; MS=309 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][O:22][Si](C(C)(C)C)(C)C)=[C:17]([O:30][C:31]([F:34])([F:33])[F:32])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[C:17]([O:30][C:31]([F:34])([F:32])[F:33])[CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CO[Si](C)(C)C(C)(C)C)c(OC(F)(F)F)c2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CO)c(OC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 4-(N-tert-butyloxy-carbonyl-4-piperidinyloxy)-1-(tert-butyldimethylsilyloxymethyl)-2-trifluoromethoxybenzene (3.5 g, 7.1 mmol) from Step 5 above in THF (50 mL) was added TBAF (8 mL of a 1.0 M solution in THF, 8 mmol). The mixture was stirred at ambient temperature for 5 minutes and the solvent was removed under reduced pressure. The residue was partitioned between EtOAc (100 mL) and water (2×50 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using a gradient elution of 25-50% EtOac:hexanes to give 4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-(trifluoromethoxy)benzyl alcohol as a colorless gum (TLC Rf =0.24 (25% EtOAc EtOAc:hexanes)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[NH:15][C:16]([C:18]1[NH:27][C:21]2=[N:22][C:23]([Cl:26])=[CH:24][CH:25]=[C:20]2[N:19]=1)=[S:17].Br.CC(O)=O.CS(C)=O.[OH-].[NH4+]>C(OCC)(=O)C.O>[Cl:26][C:23]1[N:22]=[C:21]2[NH:27][C:18]([C:16]3[S:17][C:5]4[C:6]([N:9]5[CH2:14][CH2:13][O:12][CH2:11][CH2:10]5)=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=4[N:15]=3)=[N:19][C:20]2=[CH:25][CH:24]=1
Reactant: COc1ccc(N2CCOCC2)cc1NC(=S)c1nc2ccc(Cl)nc2[nH]1
Agent: Br
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4ccc(Cl)nc4[nH]3)nc12
Reaction time: 2 h
Yield: 90.6 %

Procedure:
1.0 g 5-Chloro-3H-imidazo[4,5-b]pyridine-2-carbothioic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (2.5 mmol) was dissolved in ethyl acetate (7 ml), heated to reflux and treated with 0.87 ml HBr in AcOH (5.7M, 5.0 mmol) and 0.2 ml DMSO (3.0 mmol). Stirring at reflux was continued for 2 h. Upon cooling a precipitation formed, which was isolated and dissolved in water (2 ml). The pH was adjusted to 10 with 25% ammonium hydroxide in water. Once again a precipitation formed, which was filtered. The residue on the filter was washed with water and dried in vacuo. One obtained 0.91 g 5-chloro-2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3H-imidazo[4,5-b]pyridine (92%) as a yellow solid; M.p.: >300° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:8]=[C:7]2[O:20][CH2:21][C:22]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:23])([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O.C(OCC)C.C(O)(C)C.C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:8]=[C:7]2[O:20][CH2:21][C:22]([N:24]1[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1)=[O:23]
Reactant: O=C(COc1cc(-c2ccccc2)nc2ccc([N+](=O)[O-])cc12)N1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Nc1ccc2nc(-c3ccccc3)cc(OCC(=O)N3CCOCC3)c2c1
Temperature: 20 °C
Yield: 10 %

Procedure:
4-[(6-Nitro-2-phenyl-4-quinolyl)oxyacetyl]morpholine (12.5 g) in ethanol (550 cc) is heated under reflux for 10 minutes and a solution of sodium dithionite (27.7 g) in water (277 cc) is added in the course of 25 minutes. The mixture is cooled to room temperature (approximately 20° C.) and the ethanol removed under reduced pressure. The aqueous phase is stirred with ethyl acetate and the organic phase is washed with water, dried over magnesium sulphate and evaporated under reduced pressure. The residue obtained is taken up in ethyl ether and converted to the crude hydrochloride by adding a solution of hydrochloric acid in isopropanol. The hydrochloride is taken up with ethyl acetate and aqueous sodium carbonate solution. The precipitate which separates is filtered, heated for 25 minutes in refluxing ethyl acetate, filtered off and dried. 4-[(6-Amino-2-phenyl-4-quinolyl)oxyacetyl]morpholine (1.15 g), m.p. 194° C., is thereby isolated.
Reaction SMILES: Br.Br[CH:3]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=1)=O.[NH2:22][C:23]([NH2:25])=[S:24].C(N(CC)CC)C>C(#N)C>[CH3:13][C:12]([C:9]1[CH:10]=[CH:11][C:6]([C:4]2[N:22]=[C:23]([NH2:25])[S:24][C:3]=2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:7][CH:8]=1)([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1ccc(C(=O)C(Br)c2ccncc2)cc1
Reactant: NC(N)=S
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)c1ccc(-c2nc(N)sc2-c2ccncc2)cc1
Yield: 70 %

Procedure:
To a solution of 2-bromo-1-[4-(1,1-dimethylethyl)phenyl]-2-(4-pyridyl)ethanone hydrobromide (5.0 g, 12 mmol) and thiourea (0.95 g, 13 mmol) in acetonitrile (60 mL) was added dropwise triethylamine (1.8 ml, 13 mmol) and the mixture was refluxed for 3 h. The solvent was evaporated under reduced pressure and saturated aqueous sodium hydrogencarbonate solution was added to the residue. The precipitated solid was collected by filtration. The obtained crude crystal was recrystallized from ethanol to give the title compound (2.6 g, 8.4 mmol, yield 69%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9](C(OC(C)(C)C)=O)[C:10]2[C:15]([C:16]=1[CH:17]([CH:19]1[C:23](=[O:24])[N:22]([C:25](OC(C)(C)C)=O)N(C3C4CC5CC(CC3C5)C4)[CH2:20]1)O)=[C:14]([Cl:42])[CH:13]=[C:12]([Cl:43])[CH:11]=2)=[O:7])(C)(C)C.Cl>C(O)C>[Cl:42][C:14]1[CH:13]=[C:12]([Cl:43])[CH:11]=[C:10]2[C:15]=1[C:16](/[CH:17]=[C:19]1/[C:23](=[O:24])[N:22]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:25][CH2:20]/1)=[C:8]([C:6]([O:5][CH3:1])=[O:7])[NH:9]2
Reactant: CC(C)(C)OC(=O)c1c(C(O)C2CN(C3C4CC5CC(C4)CC3C5)N(C(=O)OC(C)(C)C)C2=O)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: COC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1/C=C1\CCN(c2ccccc2)C1=O
Temperature: 25 °C
Yield: 215.8 %

Procedure:
Intermediate 4 (700 mg) was suspended in ethanol (95%) (10 ml), hydrochloric acid (10 ml, 6M) was added and the heterogeneous mixture refluxed for 10 h. The suspension was cooled to room temperature and the solid filtered, washed with further portions of 6M hydrochloric acid and finally vacuum dried to yield the title compound (427 mg,) as a white solid.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=2)=[CH:9][C:8]=1[O:20][CH3:21].[CH3:22][S:23]SC.Cl>O1CCCC1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][CH2:15][C:16]([CH3:18])([CH3:19])[N:17]=2)=[C:9]([S:23][CH3:22])[C:8]=1[O:20][CH3:21]
Reactant: COc1cc(C2=NC(C)(C)CO2)ccc1Cl
Reactant: CSSC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1c(Cl)ccc(C2=NC(C)(C)CO2)c1SC
Temperature: -78 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
n-Butyllithium (2.5M in hexane, 54 ml) was added with cooling to a stirred solution of 2-(4-chloro-3-methoxyphenyl)-4,4-dimethyloxazoline (27.0 g) in tetrahydrofuran while maintaining the temperature below -40° C. The mixture was stirred at -78° C. overnight. A solution of dimethyl disulphide (26.5 g) in tetrahydrofuran was added dropwise and the mixture was stirred at -40° C. overnight. After allowing to warm to room temperature the mixture was treated with hydrochloric acid (2M). The organic layer was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by dry column flash chromatography eluted with a mixture of ethyl acetate and n-hexane to give 2-[4-chloro-3-methoxy-2-(methylsulphenyl)-phenyl]-4,4-dimethyloxazoline (11.1 g) as a white solid, m.p. 50°-52° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[O:18]=[C:19]1[C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][CH2:22][CH2:21][N:20]1[CH2:37][C:38](O)=[O:39].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[O:39]=[C:38]([N:10]1[CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:13]=[CH:14][CH:15]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:4]=2)[CH2:8][CH2:9]1)[CH2:37][N:20]1[CH2:21][CH2:22][CH2:23][C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]1=[O:18]
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: FC(F)(F)c1cccc(CN2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(Cc2cccc(C(F)(F)F)c2)CC1
Reaction time: 8 h

Procedure:
A solution of 1-(3-(trifluoromethyl)benzyl)piperazine (0.395 g, 1.616 mmol), 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E, 0.500 g, 1.616 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.403 g, 2.101 mmol) in dichloromethane (2 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF25-40 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 35 minutes (flow=35 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.40-7.61 (m, 4H), 7.27-7.34 (m, 8H), 7.18-7.25 (m, 2H), 4.23 (s, 2H), 3.64-3.69 (m, 2H), 3.55 (s, 2H), 3.50 (t, J=6.5 Hz, 2H), 3.43-3.49 (m, 2H), 2.60-2.67 (m, 2H), 2.38-2.49 (m, 4H), 1.79-1.89 (m, 2H); MS (ESI+) m/z 536 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](O)=[O:10])[CH:5]=[CH:6][CH:7]=1.B#B.O>O1CCCC1>[OH:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: B#B
Solvent: C1CCOC1
Solvent: O
Product: OCCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.3 %

Procedure:
To a solution of 3-bromophenylacetic acid (10 g, 46.5 mmol) in tetrahydrofuran (100 ml) at 0° C. was added diborane (70 ml, 1.0 M solution in tetrahydrofuran). The reaction mixture was allowed to warm to room temperature. After 16 h, the reaction mixture was cooled to 0° C. and water was added dropwise (50 ml). The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (elution gradient: 40-60% ethyl acetate/hexane) to give 3-(2-hydroxyethyl)bromobenzene (9.0 g).
Reaction SMILES: [CH2:1]([N:8]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:9]([C@H:20]([CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[CH2:1]([N:8]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:9]([C@H:20]([CH2:28][CH:29]([OH:32])[CH2:30][O:31][S:41]([CH3:40])(=[O:43])=[O:42])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@@H](CC(O)CO)[C@@H](C(=O)OCc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)[C@@H](CC(O)COS(C)(=O)=O)[C@@H](C(=O)OCc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
1-benzyl 4-tert-butyl(2S,3S)-2-(dibenzylamino)-3-(2,3-dihydroxypropyl)succinate from step 1 j (2.917 g, 5.47 mmol) was dissolved in pyridine (10 mL), cooled to 0° C. and MsCl (0.444 mL, 5.74 mmol) was added. The solution was stirred at 0° C. for 4 hours and diluted by 10% citric acid. The reaction mixture was extracted with EtOAc three times. The combined organic solution was washed by 10% citric acid three times, then brine, dried with MgSO4 and concentrated, the residue was purified on silica gel using 50% EtOAc/Hexane as elution to provide of 1-benzyl 4-tert-butyl(2S,3S)-2-(dibenzylamino)-3-{2-hydroxy-3-[(methylsulfonyl)oxy]propyl}succinate (2.696 g, 81%). MS (ESI): 612.1.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=2[O:10][CH3:11])=[CH:15][CH:14]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C=O)ccc1OCc1ccc(Cl)cc1
Yield: 92.6 %

Procedure:
To 4-hydroxy-3-methoxybenzaldehyde (105, 600.0 mg, 3.94 mmol) and 4-chlorobenzyl bromide (557, 1.20 g, 5.84 mmol) in acetonitrile (6 mL) was added potassium carbonate (0.390 g, 2.82 mmol). The reaction was microwaved on 300 watts, 120° C. for 10 minutes. The reaction was extracted with ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered and the volatiles removed by evaporation. The desired compound was purified by recrystallization from hexanes to provide 106 (1.01 g, 93%). MS(ESI) [M−H+]−=275.1.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]1[O:13][C:14]([CH3:17])=[CH:15][N:16]=1)=[C:5]2[O:18][CH3:19].C1(C(C2C=CC=CC=2)CCP)C=CC=CC=1.C([SiH](CCCCCC)CCCCCC)CCCCC.CN(C)[CH:57]=[O:58]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:57]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]1[O:13][C:14]([CH3:17])=[CH:15][N:16]=1)=[C:5]2[O:18][CH3:19])=[O:58]
Reactant: CN(C)C=O
Reactant: COc1c(-c2ncc(C)o2)cnc2ccc(I)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCCC[SiH](CCCCCC)CCCCCC
Product: COc1c(-c2ncc(C)o2)cnc2ccc(C=O)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40 %

Procedure:
A mixture of 6-iodo-4-methoxy-3-(5-methyl-oxazol-2-yl)-quinoline (example 16c) (492 mg, 1.34 mmol), trethylamine (0.46 mL, 3.35 mmol), diphenylpropylphosphine (dpp, 31 uL, 0.13 mmol) and palladium(II) acetate (31 mg, 0.13 mmol) in dry N,N-dimethylformamide (20 mL) in pressure tube was stirred under carbon monoxide at 75 psi at room temperature for 10 min. After addition of trihexylsilane (1.01 mL, 2.68 mmol), the mixture was then stirred under carbon monoxide at 75 psi at 80° C. for 5 h. The reaction was allowed to cool to 25° C. and then extracted with ethyl acetate (2×100 mL). The combined organic layers were successively washed with a saturated aqueous sodium bicarbonate solution (3×50 mL) and water (3×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 0%-50% ethyl acetate in hexanes in 30 min) afforded 6-formyl-4-methoxy-3-(5-methyl-oxazol-2-yl)-quinoline (144 mg, 40%) as a white solid. LC-MS m/e 269 (MH+).
Reaction SMILES: [CH:1]([C@:4]1([C:17]([N:19]2[CH2:24][CH:23]=[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[CH2:21][CH2:20]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5]1)([CH3:3])[CH3:2]>Cl.CCOCC>[CH:1]([C@:4]1([C:17]([N:19]2[CH2:20][CH:21]=[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:32])[F:33])[CH2:23][CH2:24]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)N2CC=C(c3ccccc3C(F)(F)F)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOCC
Product: CC(C)[C@]1(C(=O)N2CC=C(c3ccccc3C(F)(F)F)CC2)CC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 108.1 %

Procedure:
tert-Butyl ((1R,3S)-3-isopropyl-3-{[4-[2-(trifluoromethyl)phenyl]-3,6-dihydropyridin-1(2H)-yl]carbonyl}cyclopentyl)carbamate (0.17 g, 0.00035 mol) was dissolved in a 2.0 M solution of HCl in ether (2.2 mL). After being stirred for 2 h at room temperature, the solution was concentrated to give 144 mg of desired product as a clear oil. MS calculated for C21H27F3N2O:(M+H) 381; found 381.1.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1([C:13]#N)[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1.[C:16]1([Mg]Cl)[CH:21]=[CH:20]C=[CH:18][CH:17]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:1][N:2]([CH3:15])[C:3]1([C:13]2[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=2)[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Reactant: Cl[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
30 g 8-dimethylamino-1,4-dioxaspiro[4.5] decane-8-carbonitrile were dissolved in 300 ml tetrahydrofuran, 143 ml 2.0 molar phenyl magnesium chloride solution in THF were added under a nitrogen atmosphere and stirred overnight at ambient temperature. To work up the mixture, 100 ml ammonium chloride solution (20% by weight) were added with ice cooling, the phases were separated, the aqueous phase was extracted twice with 250 ml diethylether in each case, the combined organic phases were dried over sodium sulfate, filtered, concentrated and substantially freed from solvent residues under vacuum. The crude dimethyl-(8-phenyl-1,4-dioxaspiro[4.5]dec-8-yl)amine (34.5 g) obtained was stirred for 48 hours with a mixture of 83 ml concentrated hydrochloric acid (32% by weight) and 48 ml water at ambient temperature without further purification. Subsequently the reaction mixture was first washed three times with 50 ml diethylether in each case, then alkalized by addition of 100 ml sodium hydroxide solution (32% by weight) with ice cooling, extracted three times with 100 ml dichloromethane in each case, the combined dichloromethane extracts were dried over sodium sulfate, filtered, concentrated and substantially freed of solvent residues under vacuum. 18.8 g 4-dimethylamino-4-phenylcyclohexanone were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][CH2:10][OH:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:31][O:32][C:33](=[O:43])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36](O)[CH:35]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:31][O:32][C:33](=[O:43])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([O:11][CH2:10][CH2:9][C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[F:1])[CH:35]=1
Reactant: Cc1ccc(F)c(CCO)c1
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC)c(OCCc2cc(C)ccc2F)c1
Reaction time: 8 h
Yield: 60.5 %

Procedure:
2-(2-Fluoro-5-methyl-phenyl)-ethanol (508 mg, 3.29 mmol) was dissolved in THF (23 ml). Triphenylphosphine (1.08 g, 4.12 mmol) and 3-hydroxy-4-methoxy-benzoic acid methyl ester (500 mg, 2.75 mmol) were added, the mixture was cooled in an ice bath, and DIAD (832 mg, 4.12 mmol) was added slowly with stirring. The ice bath was removed and stirring was continued overnight at room temperature. The volatiles were evaporated in vacuo, and the residue was purified by RP HPLC (water/ACN gradient) to give 530 mg of the title compound.