Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:35]>>[Cl:35][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:7]1[O:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(CCCCCO)o1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)c1ccc(CCCCCCl)o1
Yield: 60 %

Procedure:
5-(5-Acetyl-2-furanyl)pentanol (9.8 g), 13.1 g of triphenylphosphine and 100 ml of carbon tetrachloride were combined and heated at reflux for 4 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in ether and filtered. The filtrate was concentrated and the residue distilled twice to give 2-(5-chloropentyl)-5-acetylfuran, b.p. 100°-102° C. (0.05 mm) in 60% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])C=CC=CC=1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:17]/[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C/c1cccc(F)c1

Procedure:
To a solution of 3-fluorobenzaldehyde (10 g, 80 mmol) in tetrahydrofuran (370 ml) was added tert-butyl 2-(triphenylphosphoranylidene)acetate (27.6 g, 73.3 mmol) in 1 g portions over 30 minutes. Upon final addition, the mixture was heated to reflux for 10 minutes. The solvent was removed under reduced pressure. The white waxy residue was triturated with pentane (x2). The pentane extracts were combined and evaporated under reduced pressure. The residue was purified by filtration through a plug of silica gel using an eluent of diethyl ether:hexane (1:2) to afford the title compound as a colorless oil, 16.2 g.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[O:17][CH3:18])=[CH:5][CH:4]=1.[C:19]([N:23]1[C:27](=[O:28])[CH2:26][CH:25]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][SH:36])=[CH:31][CH:30]=2)[S:24]1(=[O:38])=[O:37])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([N:23]1[C:27](=[O:28])[CH2:26][CH:25]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][S:36][CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C:9]4[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=4[O:17][CH3:18])=[CH:5][CH:4]=3)=[CH:31][CH:30]=2)[S:24]1(=[O:37])=[O:38])([CH3:22])([CH3:20])[CH3:21]
Reactant: COc1ccc(-c2ccc(CBr)cc2)c(OC)c1
Reactant: CC(C)(C)N1C(=O)CC(c2ccc(CS)cc2)S1(=O)=O
Product: COc1ccc(-c2ccc(CSCc3ccc(C4CC(=O)N(C(C)(C)C)S4(=O)=O)cc3)cc2)c(OC)c1

Procedure:
This compound was prepared according to the procedure of Example 1.35, Step 4, using 4.18-B of Step 2 and 4.15-F of Example 4.15, Step 6 as the starting materials. LCMS found for C29H34NO5S2 (M+H)+: m/z=539.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:15]=[C:14]([Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[C:13]([F:23])=[CH:12][N:11]=1.[F:24][CH:25]([F:31])[C:26](OCC)=[O:27]>C1COCC1>[Br:9][C:10]1[N:11]=[C:12]([C:26](=[O:27])[CH:25]([F:31])[F:24])[C:13]([F:23])=[C:14]([Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[CH:15]=1
Reactant: CC[Si](CC)(CC)c1cc(Br)ncc1F
Reactant: CCOC(=O)C(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc(Br)nc(C(=O)C(F)F)c1F
Reaction time: 3 h
Yield: 75 %

Procedure:
To a freshly prepared solution of LDA (6.25 mmol) in THF (5 ml) was added dropwise a solution of 2-bromo-5-fluoro-4-triethylsilanylpyridine (1.6 g, 5.51 mmol) in THF (12 ml) at −78° C. Stirring was continued at −78° C. for 3 hours. Ethyl 2,2-difluoroacetate (0.58 ml, 5.51 mmol) was added dropwise and the solution was stirred at −78° C. for 3 hours. The reaction mixture was quenched with sat. ammonium chloride solution (20 ml) and ethyl acetate was added. The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated. The crude brown oil (2.11 g) was chromatographed over silica gel (cyclohexane/ethyl acetate) to give the title compound. 1.53 g (75% yield, mixture of ketone and hydrate form).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=O.[OH:9][C:10]1[CH:11]=[C:12]([C:16]23[CH2:23][CH:20]([NH:21][CH2:22]2)[CH2:19][CH2:18][CH2:17]3)[CH:13]=[CH:14][CH:15]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.N>O1CCCC1.O.CN(C)C=O.C(N(CC)CC)C>[OH:9][C:10]1[CH:11]=[C:12]([C:16]23[CH2:23][CH:20]([N:21]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:22]2)[CH2:19][CH2:18][CH2:17]3)[CH:13]=[CH:14][CH:15]=1
Reactant: Oc1cccc(C23CCCC(C2)NC3)c1
Reactant: CCCCCC(=O)Cl
Agent: Cl
Agent: N
Agent: [Al+3]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCN1CC2(c3cccc(O)c3)CCCC1C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.9 %

Procedure:
0.73 g of n-caproyl chloride is added to a mixture of 0.5 g of 1-(3-hydroxyphenyl)-6-azabicyclo[3,2,1]octane, 0.62 g of triethylamine and 10 ml of dimethylformamide. The mixture is stirred at room temperature for 4 hours. Then, water is added to the mixture, and the aqueous mixture is extracted with chloroform. The chloroform extract is washed with water, dried and then evaporated to remove solvent. The residue thus obtained is dissolved in 40 ml of tetrahydrofuran. 0.9 g of lithium aluminium hydride is added to the solution, and the solution is refluxed for 12 hours under heating. After cooling, water is added to the reaction solution to decompose lithium aluminium hydride. The reaction solution is acidified with hydrochloric acid. Then, the reaction solution is made alkaline with aqueous ammonia and extracted with chloroform. The chloroform extract is washed with water, dried and then evaporated to remove solvent. The residue is dissolved in 5 ml of chloroform. The chloroform solution is poured onto the column of 50 g of silica gel. Then, the column is eluted with a mixture of 950 ml of chloroform and 50 ml of methanol, and the effluent is evaporated to remove solvent. The residue thus obtained is distilled under reduced pressure, whereby 0.48 g of 1-(3-hydroxyphenyl)-6-n-hexyl-6-azabicyclo[3,2,1]octane is obtained as a viscous oil boiling at 250°C(bath temperature/0.1 mmHg.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)[CH:5]=1.[OH-].[Na+]>CO.C1COCC1.O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([S:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:18])=[O:2])=[N:12][CH:13]=1
Reactant: COC(=O)c1cccc(Sc2ccc(Cl)cn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(Sc2ccc(Cl)cn2)c1
Yield: 78 %

Procedure:
A solution of 3-(5-chloro-pyridin-2-ylsulfanyl)-benzoic acid methyl ester (780 g, 2.8 mmol) and NaOH (500 mg, 12 mmol) in methanol:THF:water (1:1:1, 6 mL) was stirred at room temperature for 8 h. Solvents were evaporated. Crude mass was taken in water (40 mL), acidified to pH 4.0 and extracted with ethyl acetate. Evaporation of ethyl acetate provided 3-(5-chloro-pyridin-2-ylsulfanyl)-benzoic acid (580 mg).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C@H:14]([C:19]([OH:21])=O)[CH2:15][C:16](=[O:18])[NH2:17])=[O:12].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[OH:54][C@H:55]([C@@H:73]([NH2:81])[CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[CH2:56][N:57]([CH2:66][CH:67]1[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]1)[NH:58][C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60]>C1COCC1>[OH:54][C@H:55]([C@@H:73]([NH:81][C:19](=[O:21])[C@H:14]([CH2:15][C:16](=[O:18])[NH2:17])[NH:13][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12])[CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[CH2:56][N:57]([CH2:66][CH:67]1[CH2:68][CH2:69][CH2:70][CH2:71][CH2:72]1)[NH:58][C:59]([O:61][C:62]([CH3:65])([CH3:63])[CH3:64])=[O:60]
Reactant: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)O
Reactant: CC(C)(C)OC(=O)NN(CC1CCCCC1)C[C@H](O)[C@@H](N)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN(CC1CCCCC1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
At 5° C., 940 mg (3.27 mmol) of quinoline-2-carbonyl-(L)-asparagine (in the form of the hydrochloride salt) are dissolved in 35 ml of THF, and 736 mg (3.57 mmol) of DCC are added. After 10 min, 482 mg (3.57 mmol) of HOBT, 0.82 ml (7.44 mmol) of NMM and 1.165 g (2.98 mmol) of 1-[2(S)-hydroxy-3(S)-amino-4-phenyl-butyl]-1-[cyclohexylmethyl]-2-[tert-butoxycarbonyl]-hydrazine are added and the mixture is stirred at RT for 18 h. The reaction mixture is filtered and the filtrate is concentrated by evaporation. The residue is partitioned between 3 portions of ethyl acetate, saturated NaHCO3 solution, water and brine, and the organic phases, which have been dried with Na2SO4, are concentrated by evaporation and subjected to column chromatography (SiO2, ethyl acetate) to yield the title compound: TLC Rf (O)=0.16; tRet (V)=16.5 min; FAB-MS (M+H)+ =661.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12]([O:22][CH3:23])[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[F:31].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:24][C:25]1[CH:26]=[C:27]([C:2]2[CH:3]=[C:4]3[C@:15]4([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]4)[C:14]4[CH:13]=[C:12]([O:22][CH3:23])[N:11]=[CH:10][C:9]=4[O:8][C:5]3=[CH:6][CH:7]=2)[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: COc1cc2c(cn1)Oc1ccc(Br)cc1[C@@]21COCC(N)=N1
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Product: COc1cc2c(cn1)Oc1ccc(-c3ccc(F)c(F)c3)cc1[C@@]21COCC(N)=N1
Temperature: 100 °C
Yield: 89.4 %

Procedure:
A microwave vial was charged with (S)-7-bromo-3-methoxy-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.075 g, 0.199 mmol). 3,4-difluorophenylboronic acid (0.063 g, 0.399 mmol), potassium phosphate (0.127 g, 0.598 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (7.06 mg, 9.97 μmol) were added. The vial was flushed with Ar (g), then dioxane (0.748 mL) and water (0.249 mL) were added in sequence. The vial was sealed and heated in a Biotage Initiator microwave reactor for 30 min at 100° C. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (0-100% EtOAc/Hexanes) to afford (S)-7-(3,4-difluorophenyl)-3-methoxy-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.073 g, 0.178 mmol, 89% yield) as an off-white solid. [M+H]+=410.4
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([CH3:13])=[N:4][CH:3]=1.[CH2:14](B(O)O)[CH:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:14]([C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([CH3:13])=[N:4][CH:3]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: CCOC(=O)c1nc(Cl)cnc1C
Reactant: CC(C)CB(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(CC(C)C)cnc1C
Temperature: 100 °C

Procedure:
A suspension of ethyl 6-chloro-3-methylpyrazine-2-carboxylate (1.94 g, 9.67 mmol), isobutylboronic acid (1.97 g, 19.3 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(212 mg, 0.290 mmol), and potassium carbonate (2.67 g, 19.3 mmol) in 1,4-dioxane (30 mL) was heated at 100° C. for 4.5 h. After being cooled to ambient temperature, the reaction mixture was diluted with ethyl acetate and filtrated through celite with ethyl acetate. The filtrate was combined and concentrated in vacuo. The residue was diluted ethyl acetate, and washed with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium bicarbonate, filtrated and concentrated in vacuo. The residue was dissolved to dichloromethane, and the insoluble materials were filtered off. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 3:1) to give ethyl 6-isobutyl-3-methylpyrazine-2-carboxylate. MS (APCI): m/z 223 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH2:19][C:20]([O:22]CC)=[O:21])=[CH:10][CH:9]=2)=[O:7])=[C:4]([CH3:27])[CH:3]=1.I>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH2:19][C:20]([OH:22])=[O:21])=[CH:12][CH:13]=2)=[O:7])=[C:4]([CH3:27])[CH:3]=1
Reactant: CCOC(=O)CC1CCCN1c1ccc(C(=O)c2ccc(Cl)cc2C)cc1
Agent: I
Product: Cc1cc(Cl)ccc1C(=O)c1ccc(N2CCCC2CC(=O)O)cc1
Yield: 36 %

Procedure:
Example 89 (pale yellow oil, 0.017 g, 0.047 mmol, 36% yield) was prepared from ethyl 2-(1-(4-(4-chloro-2-methylbenzoyl)phenyl)pyrrolidin-2-yl)acetate (88E) following the procedure of 86H. LC-MS Anal. Calc'd for C20H20ClNO3 357. found [M+H] 358. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.4 (1H, brs), 7.55 (2H, d, J=8.8 Hz), 7.43 (1H, d, J=1.2 Hz), 7.36 (1H, dd, J=1.2, 8.0 Hz), 7.24 (1H, d, J=8.0 Hz), 6.62 (2H, d, J=8.8 Hz), 4.17 (1H, m), 3.47 (1H, m), 3.22 (1H, m), 2.58 (1H, m), 2.30 (1H, m), 2.17 (3H, s), 2.06 (3H, m), 1.99 (1H, m). Analytical HPLC: RT=18.7 min, HI: 92.9%.
Reaction SMILES: [CH2:1]([O:19][CH:20]([CH2:28][CH3:29])[C:21]([O:23]C(C)(C)C)=[O:22])[CH2:2]/[CH:3]=[CH:4]\[CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH3:18]>C(O)=O.C(OCC)C>[CH2:1]([O:19][CH:20]([CH2:28][CH3:29])[C:21]([OH:23])=[O:22])[CH2:2]/[CH:3]=[CH:4]\[CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH3:18]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCOC(CC)C(=O)OC(C)(C)C
Solvent: O=CO
Solvent: CCOCC
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCOC(CC)C(=O)O
Temperature: 40 °C
Reaction time: 6 h
Yield: 67.4 %

Procedure:
A mixture of tert-butyl 2-((3Z,6Z,9Z,12Z,15Z)-octadeca-3,6,9,12,15-pentaen-1-yloxy)butanoate (2.09 g, 4.58 mmol) in HCOOH (9 mL) was stirred at 40° C. under N2-atmosphere for 6 hrs. The reaction mixture was diluted with diethyl ether (100 mL), washed with water (30 mL), dried (MgSO4), filtered and evaporated under reduced pressure. Dry-flash on silica gel (50 g) eluting with toluene-toluene/EtOAc (85:15) yielded 1.44 g of the crude title compound. Flash chromatography on silica gel (30 g) eluting with heptane-heptane/(EtOAc w/5% HCCOH) 98:2-95:5-80:20 yielded 1.07 g (58% yield) of the title compound as a liquid. 1H NMR (200 MHz, CDCl3) δ 0.97 (t, 3H), 0.99 (t, 3H), 1.75-1.91 (m, 2H), 2.00-2.15 (m, 2H), 2.35-2.48 (m, 2H), 2.78-2.87 (m, 8H), 3.47-3.62 (m, 2H), 3.86 (dd, 1H), 5.25-5.55 (m, 10H). MS (electrospray) (neg): 345 (M−H)−.
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)(O)[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.S(Cl)(Cl)=O.[OH-].[K+]>C(Cl)Cl.O>[CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6](/[CH:14]=[C:15](/[C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)\[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cnccn2)CCN(C)C1
Agent: [K+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1cnccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-(pyrazin-2-yl)propan-2-ol (336 mg, 1.0 mmol) in DCM (8 mL) was added at 0° C. a solution of thionyl chloride (594 mg, 5 mmol) in DCM (8 mL). The reaction mixture was stirred at RT for 30 min., volatiles were evaporated under reduced pressure and the residue was dissolved in N-methyl-2-pyrrolidone (4 mL). KOH (392 mg, 7.0 mmol) was added and the reaction mixture was stirred at RT for 5 min. and at 100° C. for 30 min. The reaction mixture was cooled to RT, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and the residue purified by HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 9.0 (d, 1H), 8.70 (s, 1H), 8.60 (d, 1H), 7.70 (s, 1H), 7.38 (s, 1H), 7.15 (m, 2H), 4.78 (d, 1H), 4.40 (d, 1H), 3.90 (m, 1H), 3.60 (m, 1H), 3.25 (m, 2H), 3.20 (s, 3H), 2.50 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=[O:2].[CH:8]([C:11]1[CH:12]=[CH:13][C:14]([CH3:54])=[C:15]([N:17]2[CH2:53][CH2:52][C:20]3[N:21]=[C:22]([C:32]4[CH:40]=[CH:39][CH:38]=[C:37]5[C:33]=4[C:34]([CH3:51])=[CH:35][N:36]5[S:41]([C:44]4[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=4)(=[O:43])=[O:42])[N:23]=[C:24]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][C@H:26]4[CH3:31])[C:19]=3[CH2:18]2)[CH:16]=1)([CH3:10])[CH3:9].C(OC(=O)C)(=O)C.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[CH:8]([C:11]1[CH:12]=[CH:13][C:14]([CH3:54])=[C:15]([N:17]2[CH2:53][CH2:52][C:20]3[N:21]=[C:22]([C:32]4[CH:40]=[CH:39][CH:38]=[C:37]5[C:33]=4[C:34]([CH3:51])=[CH:35][N:36]5[S:41]([C:44]4[CH:45]=[CH:46][C:47]([CH3:48])=[CH:49][CH:50]=4)(=[O:42])=[O:43])[N:23]=[C:24]([N:25]4[CH2:30][CH2:29][N:28]([C:1](=[O:2])[CH3:3])[CH2:27][C@H:26]4[CH3:31])[C:19]=3[CH2:18]2)[CH:16]=1)([CH3:10])[CH3:9]
Reactant: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc5c(c(N6CCNC[C@H]6C)n4)CN(c4cc(C(C)C)ccc4C)CC5)cccc32)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCN(c2nc(-c3cccc4c3c(C)cn4S(=O)(=O)c3ccc(C)cc3)nc3c2CN(c2cc(C(C)C)ccc2C)CC3)[C@H](C)C1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
The TFA salt of (R)-6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-4-(2-methylpiperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (62 mg, 0.095 mmol) was dissolved in DCM (5 mL) and acetic anhydride (0.014 mL, 0.143 mmol) and DIEA (0.133 mL, 0.764 mmol) were added. The reaction was stirred at rt for 45 min and diluted with EtOAc, and washed successively with sat NaHCO3 and brine. The organic layer was then dried over Na2SO4 and filtered. After concentration, the resulting residue was purified by FCC (60-90% EtOAc/heptane) to provide (R)-1-(4-(6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)ethanone. MS (ESI+) m/z 691.4 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.C(Cl)(Cl)Cl.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C1C=CN=CC=1.O.C(OCC)(=O)C>[C:23]([O:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccc(CCO)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(CCOC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
Next, to a mixture of 4-(2-hydroxyethyl)benzaldehyde (6.3 g, 42.2 mmol) and chloroform (170 mL), triethylamine (5.1 g, 50.6 mmol), benzoyl chloride (7.1 g, 50.6 mmol) and 4-dimethylaminopyridine (515 mg, 4.2 mmol) were added at 0° C. The reaction mixture was stirred at room temperature for 2 hours, poured into a mixture of ethyl acetate and water, and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After concentration, the resulting residue was purified by neutral silica gel column chromatography (hexane:ethyl acetate=20:1 to 10:1) to give 4-(2-benzoyloxyethyl)benzaldehyde (5.4 g).
Reaction SMILES: [N:1]1([C:7](OCC)=O)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]C.CC(=O)CC>O>[CH2:7]([N:1]1[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCBr
Reactant: CCOC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCCCCCCCCCN1CCNCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 13.1 %

Procedure:
A mixture of 2.02 g of ethyl 1-piperazinecarboxylate, 1.92 g of anhydrous potassium carbonate, 3.08 g of decyl bromide and 20 ml of 2-butanone was stirred overnight at 80° C. After addition of water, the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was extracted with 3N hydrochloric acid. The extract was made alkaline with potassium carbonate and then extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure Ethanol (20 ml) and ml of 10% aqueous sodium hydroxide were added to the residue, and the mixture was stirred overnight at 100° C. The reaction mixture was cooled and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.38 g of 1-decylpiperazine as an oil.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:17]1([NH2:20])[CH2:19][CH2:18]1.O>CN(C)P(N(C)C)(N(C)C)=O.C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH:17]1([N:20]=[C:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]2=3)[CH2:19][CH2:18]1
Reactant: NC1CC1
Reactant: O=C1c2ccccc2CCc2ccccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: c1ccccc1
Solvent: O
Product: c1ccc2c(c1)CCc1ccccc1C2=NC1CC1
Temperature: 25 °C

Procedure:
To a solution of 5 g of 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one and 20 g of cyclopropylamine in 25 ml of hexamethylphosphoramide is added, with cooling, during 30 minutes, a solution of 1.7 ml of titanium tetrachloride in 10 ml of anhydrous benzene. After stirring at room temperature for 2 weeks, benzene (50 ml) and water (50 ml) are added, with cooling. The mixture is filtered, the layers of the filtrate are separated, and the aqueous phase is extracted with 50 ml of benzene. The combined aqueous phases are washed with 5% aqueous sodium bicarbonate solution (25ml) and water (3 × 25 ml) and dried with magnesium sulfate. The solvent is removed, and the residue is shortpath distilled at a bath temperature of 145°-150° (0.3 micron) to give N-cyclopropyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5-imine as a solid. Nmr spectrum (in CDCl3): multiplets at τ 2.3-3.0 (8H) 6.6-7.2 (5H) and 8.2-9.4 (4H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:23]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([Cl:23])[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)NCC(O)c1ccc2ccccc2c1
Product: CC(C)(C)OC(=O)NCC(Cl)c1ccc2ccccc2c1

Procedure:
16 g of 2-t-butoxycarbonylamino-1-(2-naphthyl)ethanol [prepared as described in step (a) above] were chlorinated with phosphorus pentachloride in the same manner as in Example 36(b) to give 9.1 g of the crystalline title compound, melting at 97°-98° C.