Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].[OH:4][C@H:5]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:27])[C@:11]3([OH:28])[CH2:12][CH2:13][C@@H:14]2/[CH:15]=[CH:16]/[CH:17]=O)[CH2:6]1>[OH-].[Na+].O1CCOCC1.O>[OH:3]/[N:2]=[CH:17]/[CH:16]=[CH:15]/[C@H:14]1[CH2:13][CH2:12][C@:11]2([OH:28])[C@H:10]3[C@H:22]([CH2:21][CH2:20][C@:19]12[CH3:27])[C@:23]1([CH3:26])[C@@H:7]([CH2:6][C@@H:5]([OH:4])[CH2:25][CH2:24]1)[CH2:8][CH2:9]3
Reactant: NO
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=C/C=O)CC[C@]12O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=C/C=N/O)CC[C@]12O
Yield: 63.9 %

Procedure:
To a solution of 0.65 g of hydroxylamine hydrochloride in 41 ml of 1N NaOH and 30 ml of dioxane a solution of 2.70 g of (E)-3β,14β-dihydroxy-5β-pregn-20-ene-21-carboxaldehyde (Fullerton D. S. et al., J. Med. Chem., 1976, 19,1330) in 40 ml of dioxane was added dropwise at room temperature. After 20 hrs the solution was diluted with water and extracted with methylene chloride. The crude product was purified by flash chromatography (SiO2) using hexane/ethyl acetate 1/1 as the eluant. The fractions containing the title compound were collected and evaporated to dryness. The residue was ground with di-iso-propyl ether to give 1.80 g of the title compound (I-am), as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:15]([F:17])[F:16])[NH:13][C:12](=O)[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19].C(OCC)(=O)C>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:15]([F:17])[F:16])[NH:13][C:12](=[S:19])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1COCC(c2cccc(Br)c2)(C(F)F)N1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: FC(F)C1(c2cccc(Br)c2)COCC(=S)N1

Procedure:
5-(3-Bromo-phenyl)-5-difluoromethyl-morpholin-3-one (6.10 g, 19.93 mmol) was dissolved in 63 ml dry pyridine, and P2S5 (5.32 g, 23.91 mmol) was added. The mixture was heated to 80° V for 2 hrs. After completion, the mixture was put between ethyl acetate and 1 H HCl solution. Phases were separated and the organic phase was washed with 1 N HCl, saturated NaHCO3 solution and brine. The organic phases were combined, dried over Na2SO4 and concentrated under reduced pressure to yield the title compound as off-white solid. 1H-NMR (360 MHz, DMSO-d6): 8.60 (s, 1H, NH), 7.80-7.35 (m, 4H), 6.54 (t, 1H, CHF2), 4.45 (m, 2H), 4.28 (d, 1H), 4.12 (d, 1H); MS: 322 [(M+H)+].
Reaction SMILES: [I:1][C:2]1[C:21]([C:22]([O:24]CC)=[O:23])=[C:5]2[CH2:6][N:7]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:8]([C:10]([F:13])([F:12])[F:11])[CH2:9][N:4]2[N:3]=1.[OH-].[Na+]>C(O)C.O>[C:17]([O:16][C:14]([N:7]1[CH:8]([C:10]([F:11])([F:12])[F:13])[CH2:9][N:4]2[N:3]=[C:2]([I:1])[C:21]([C:22]([OH:24])=[O:23])=[C:5]2[CH2:6]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)c1c(I)nn2c1CN(C(=O)OC(C)(C)C)C(C(F)(F)F)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1Cc2c(C(=O)O)c(I)nn2CC1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.8 %

Procedure:
To a solution of Intermediate 346D (0.22 g, 0.450 mmol) in ethanol (2 mL) and water (2 mL) was added NaOH (0.036 g, 0.899 mmol) and the solution was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure and the pH of the crude product was adjusted to 2 with an aqueous solution of 1.5N HCl and extracted with EtOAc (2×20 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and the filtrate concentrated under reduced pressure to afford Intermediate 346E as a white solid (0.12 g, 55%). MS(ES): m/z=462.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.4 (br, s., 1H), 5.55-5.38 (m, 1H), 5.18-5.08 (m, 1H), 4.54 (m, 3H), 1.48 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C(OCC)C.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]>[N:13]1([C:2]2[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: COC(=O)Cc1cccc(Br)c1
Reactant: C1COCCN1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cccc(N2CCOCC2)c1
Temperature: 100 °C
Yield: 23 %

Procedure:
A round bottom flasked flushed with argon was charged with methyl 3-bromophenyl-acetate (2.29 g, 10 mmol) (prepared from 3-bromophenylacetic acid as described in example 2, step 1), morpholine (1.05 mL, 1.2 eq.), CsCO3 (4.55 g, 1.4 eq.), Pd2(dba)3 (92 mg, 0.01 eq) and BINAP (93 mg, 0.15 eq.) in toluene (20 mL). The resulting mixture was heated at 100° C. overnight and then diluted with diethyl ether (120 mL). The precipitates were filtered through a Celite pad and the filtrate was concentrated and purified on a silica-gel column with 20% EtOAc in hexane to give methyl 3-(morpholin-4-yl)phenylacetate (0.55 g, 23%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:36][C:37]1[S:38][C:39]([CH:43]=[O:44])=[C:40]([Cl:42])[N:41]=1>>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([CH:43]([C:39]2[S:38][C:37]([Cl:36])=[N:41][C:40]=2[Cl:42])[OH:44])[C:23]([F:35])=[C:24]([Cl:34])[C:25]=1[N:26]1[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1sc(Cl)nc1Cl
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc(C(O)c3sc(Cl)nc3Cl)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45) and 2,4-dichlorothiazole-5-carbaldehyde.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:16]#[C:17][NH2:18]>Cl.O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:12][C:17]([NH2:18])=[NH:16])[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CN
Reactant: Nc1cccc(OCc2ccccc2)c1
Agent: Cl
Solvent: C1COCCO1
Product: N=C(N)Nc1cccc(OCc2ccccc2)c1
Temperature: 120 °C
Yield: 37.3 %

Procedure:
3-benzyloxy aniline (1 g, 5 mmol) and cyanamide (420 mg, 10 mmol) were dissolved in 4 mL of 4N HCl in dioxane and heated to 120° C. overnight. The reaction mixture was cooled to room temperature, quenched with water, and extracted with diethyl ether. The aqueous layer was made basic with 2N NaOH and extracted thrice with dichloromethane. The organic extracts were combined and washed with brine, dried over MgSO4, and concentrated to afford 4 (450 mg) as a light brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:9][N:8]([S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCNCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(S(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A mixture of 0.5 g (1.936 mmol) 4-tert-Butoxycarbonylamino-piperidine-4-carboxylic acid methyl ester, 0.387 g (2.03 mmol) p-toluenesulfonyl chloride and 0.587 g (5.8 mmol) NEt3 in 6 mL DCM was stirred at room temperature over night. DCM and NaHCO3 aq. was added and the organic layer was separated and dried with MgSO4. After evaporation the residue was dried under high vacuum and used without further purification. 0.796 g (95%) of the title compound was obtained as white foam. MS (m/e): 413.2 [(M+H)+].
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[NH:6][C:5]2=O.O=P(Cl)(Cl)[Cl:19]>>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[N:6]=[C:5]2[Cl:19]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(C(F)(F)F)nc2ccc(I)cc12
Product: FC(F)(F)c1nc(Cl)c2cc(I)ccc2n1

Procedure:
6-iodo-2-trifluoromethyl-3H-quinazolin-4-one (3.1 g, 9.1 mmole) was mixed with 20 mL of POCl3, heated to reflux for 3 h, removed most of unreacted POCl3 under vacuo. The residue was extracted with 15 mL of NaHCO3 (sat) and 200 mL of ether, ether layer was dried with MgSO4 and concentrated to give the light yellow solid 3.05 g, mp 145°-146° C., MS (CI): m/z 359 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:37]=1[C:38](Cl)=[O:39]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:38](=[O:39])[C:37]3[C:36]([F:35])=[CH:44][CH:43]=[CH:42][C:41]=3[F:45])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N(Cc3ccc4ccc(C#N)cc4c3)C(=O)c3c(F)cccc3F)cc2)CC1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, 2,6-difluorobenzoyl chloride.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:21]([O:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[C:38]([C:39]#[N:40])=[C:37]([NH:41][CH2:42][CH2:43][CH3:44])[N:36]=[C:35]([S:45][CH2:46][C:47]3[N:48]=[C:49]([C:52]4[CH:57]=[CH:56][C:55]([Cl:58])=[CH:54][CH:53]=4)[S:50][CH:51]=3)[C:34]=2[C:59]#[N:60])=[CH:29][CH:28]=1)=[O:22])[CH2:10][CH2:11][CH2:12][NH:13]C(OC(C)(C)C)=O)=O)(C)(C)C.[F:61][C:62]([F:67])([F:66])[C:63]([OH:65])=[O:64]>ClCCl>[F:61][C:62]([F:67])([F:66])[C:63]([OH:65])=[O:64].[F:61][C:62]([F:67])([F:66])[C:63]([OH:65])=[O:64].[NH2:8][C@H:9]([C:21]([O:23][CH2:24][CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[C:38]([C:39]#[N:40])=[C:37]([NH:41][CH2:42][CH2:43][CH3:44])[N:36]=[C:35]([S:45][CH2:46][C:47]3[N:48]=[C:49]([C:52]4[CH:53]=[CH:54][C:55]([Cl:58])=[CH:56][CH:57]=4)[S:50][CH:51]=3)[C:34]=2[C:59]#[N:60])=[CH:31][CH:32]=1)=[O:22])[CH2:10][CH2:11][CH2:12][NH2:13]
Reactant: CCCNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCOC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)c1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCOC(=O)[C@@H](N)CCCN)cc2)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60 mg (0.068 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(propylamino)pyridin-4-yl)phenoxy}ethyl N2, N5-bis(tert-butoxycarbonyl)-L-ornithinate (Example 20A) were initially charged in 1.8 ml dichloromethane. 0.211 ml (2.738 mmol) of trifluoroacetic acid was added, and the reaction solution was then stirred at RT overnight. The reaction solution was concentrated by evaporation and the residue was purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 55 mg (89% of theory) of the target compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([Mg]Br)=[CH:12][CH:11]=1>O1CCCC1.CCOCC>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[OH:8])=[CH:12][CH:11]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: O=Cc1cccnc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(c1ccc(F)cc1)c1cccnc1
Temperature: 0 °C
Yield: 93 %

Procedure:
A solution of 3-pyridinecarboxaldehyde (5.32 g, 49.7 mmol) in tetrahydrofuran (100 ml) was cooled to-78° C. and treated dropwise with 25 ml (50 mmol) of a 2 M solution of 4-fluorophenyl magnesium bromide in ether. The reaction mixture was then slowly warmed up to 0° C. over 1 h and then quenched by the addition of saturated aqueous sodium bicarbonate and ethyl acetate. The organic phase was washed with brine, dried (magnesium sulfate) and concentrated under reduced pressure. Filtration of the residue on a short silica gel pad (elution ethyl acetate) followed by distillation in vacuo gave 9.42 g (93%) of the title material as a clear oil which crystallized upon standing. bp 120-130° C./0.2 torr (bulb to bulb distillation, air bath temperature), mp 45-47° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 5.88 (1H, s, CH benzhydryl), 7.05 (2H, m, aromatics), 7.25-7.36 (3H, m, aromatics), 7.73 (1H, d, J=7.9 Hz, aromatic), 8.44 (1H, d, J=5.2 Hz, aromatic), 8.55 (1H, s, aromatic). Anal. Calcd for C12H10FNO: C, 70.92; H, 4.96; N, 6.89. Found: C, 70.61; H, 4.86; N, 6.71.
Reaction SMILES: [C:1]([OH:13])(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[C:14]1([CH2:24][CH2:25]O)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>>[C:14]1([CH2:24][CH2:25][O:12][C:1](=[O:13])/[CH:2]=[CH:3]/[C:4]2[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: OCCc1cccc2ccccc12
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Product: O=C(/C=C/c1ccc(O)c(O)c1)OCCc1cccc2ccccc12

Procedure:
Reaction of caffeic acid and 2-(1-naphthyl)ethanol as outlined in method A except that the reaction time was increased to 6 days, provided product 67H-148-A as a snow-white solid in 21% overall yield: mp 165°-168° C.; 1H NMR (DMSO-d6) δ:8.21 (d, 1H, J=8.1 Hz), 7.97-7.94 (m, 1H), 7.84 (t, 1H, J=5 Hz), 7.64-7.39 (m, 5H), 7.03 (d, 1H, J=1.8 Hz), 6.99 (dd, 1H, J=1.8 Hz & 8.1 Hz), 6.23 (d, 1H, J=15.9 Hz), 4.44 (t, 2H, J=7.0 Hz), 3.45 (t, 2H, J=7.0 Hz); FABMS (NBA, -VE) m/z 333 (M--H). Anal. (C21H18O4.1/4H2O) C, H.
Reaction SMILES: [CH2:1](Br)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[CH3:12][NH:13][CH3:14]>C(O)C>[CH3:12][N:13]([CH3:14])[CH2:1][CH:2]=[C:3]([CH3:4])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9]
Reactant: CC(C)=CCC/C(C)=C/CBr
Reactant: CNC
Solvent: CCO
Product: CC(C)=CCCC(C)=CCN(C)C
Yield: 72 %

Procedure:
Geranylbromide (20 g) in ethanol (50 ml) was added to 33% dimethylamine in industrial methylated spirits (240 ml) and the mixture was heated at reflux for 8 hours. The reaction mixture was evaporated to dryness, mixed with 2N sodium hydroxide (50 ml) and then extracted with diethyl ether (2×100ml). The ether extracts were combined and washed with water (50 ml), then dried with anhydrous magnesium sulphate and evaporated to dryness. The resulting orange oil was purified by chromatography (with a gradient CH2Cl2 :MeOH system as eluent) to give 1-dimethylamino-3.7-dimethyl-2,6-octadiene as an oil (12.1 g, 72%).
Reaction SMILES: C[Si]([N:5]=[N+:6]=[N-:7])(C)C.[N:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:33]=[CH:32][C:19]([O:20][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)=[CH:18][CH:17]=2)=[CH:10][CH:9]=1>>[N:8]1[CH:9]=[CH:10][C:11]([C:14]2[NH:7][N:6]=[N:5][C:15]=2[C:16]2[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)=[CH:32][CH:33]=2)=[CH:12][CH:13]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C(#Cc1ccc(OCc2ccc3ccccc3n2)cc1)c1ccncc1
Product: c1ccc2nc(COc3ccc(-c4nn[nH]c4-c4ccncc4)cc3)ccc2c1
Temperature: 150 °C
Yield: 85.2 %

Procedure:
Trimethylsilylazide (730 mg, 6.4 mmol) and 2-((4-(2-(pyridin-4-yl)ethynyl)phenoxy)methyl)quinoline (360 mg) were combined in a screw cap sealed tube and heated behind a safety shield in a 150° C. bath for 72 h. The mixture was concentrated and the yellow residue triturated with ether (2×10 mL) leaving a yellow solid (346 mg) which was chromatographed on silica eluted with a gradient of 0.5%-2% methanol in dichloromethane giving a yellow solid (210 mg, 52%). 1H NMR (CDCl3 with a drop of CD3OD, 400 mHz) 68.54 (d, 2H, J=6.2 Hz), 8.23 (d, 1H, J=8.7 Hz), 8.07 (d, 1H, J=8.7 Hz), 7.84 (d, 1H, J=7.9 Hz), 7.74 (ddd, 1H, J=8.4, 7, 1 Hz), 7.69 (d, 1H, J=8.7 Hz), 7.63 (d, 2H, J=6.2 Hz), 7.56 (ddd, 1H), 7.41 (m, 2H), 7.09 (m, 2H), 5.41 (s, 2H). MS (AP+) m/e 380 (MH+).
Reaction SMILES: Cl[C:2]1[C:21]([C:22]#[N:23])=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:24]1[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]1.CCN(C(C)C)C(C)C>CC(O)C>[C:22]([C:21]1[C:2]([N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[N:3][CH:4]=[C:5]([CH:20]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)=[O:7])#[N:23]
Reactant: N#Cc1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1Cl
Reactant: O[C@@H]1CCNC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1N1CC[C@@H](O)C1
Temperature: 110 °C

Procedure:
A stirred mixture of 6-chloro-5-cyano-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 70.3, 4.50 g, 13.2 mmol), (R)-3-Pyrrolidinol (1.38 g, 15.8 mmol) and DIPEA (3.74 g, 29.0 mmol) in iPrOH (20 mL) was heated at 110° C. for 60 min. The cooled RM was then evaporated to dryness under reduced pressure and the residue was dissolved in EtOAc, washed with sat. aq. NaHCO3 and brine. The solution was dried over anhydrous Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by crystallization from DCM/TBME to afford the product as a colorless crystalline solid. m.p. 234-236° C., HPLC (Condition 4) tR=5.41 min, UPLC-MS (Condition 8) tR=1.01 min, m/z=393.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.00-1.25 (m, 1H), 1.80-2.06 (m, 1H), 3.67 (d, J=11.34 Hz, 1H), 3.82 (br. s, 3H), 4.01 (q, J=7.04 Hz, 1H), 4.40 (br. s, 1H), 7.34 (d, J=8.60 Hz, 2H), 7.83 (d, J=8.99 Hz, 2H), 8.51 (d, J=2.35 Hz, 1H), 8.83 (d, J=2.35 Hz, 1H), 10.23 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:13][C:14]([CH3:25])([CH3:24])[C:15]([C:17]4[CH:22]=[CH:21][N:20]=[C:19](F)[CH:18]=4)=[CH:16]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[N:26]1([CH2:32][CH2:33][O:34][CH2:35][CH2:36][OH:37])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.O>CS(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:13][C:14]([CH3:24])([CH3:25])[C:15]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([N:29]5[CH2:28][CH2:27][N:26]([CH2:32][CH2:33][O:34][CH2:35][CH2:36][OH:37])[CH2:31][CH2:30]5)[CH:18]=4)=[CH:16]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccnc(F)c1
Reactant: OCCOCCN1CCNCC1
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccnc(N2CCN(CCOCCO)CC2)c1
Temperature: 105 °C

Procedure:
A mixture of (3E)-6-fluoro-3-[4-(2-fluoropyridin-4-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one (50 mg, 0.15 mmol) and 2-(2-(piperazin-1-yl)ethoxy)ethanol (50 mg, 0.29 mmol) in 2 mL of DMSO was heated in 105° C. bath for 6 hours. The mixture was cooled to room temp and poured into 100 mL of water. The precipitates were filtered, washed with water and dried in vacuo to give (3E)-6-fluoro-3-[4-(2-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}pyridin-4-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as a brown solid. Yield: 64 mg, 89%.
Reaction SMILES: [OH:1][CH:2]1[C:7]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][C:11]([O:16][CH3:17])=[CH:10][C:9]=2[O:18][CH3:19])=[CH:6][CH2:5][N:4]([CH3:20])[CH2:3]1>O>[OH:1][C@H:2]1[C@@H:7]([C:8]2[C:9]([O:18][CH3:19])=[CH:10][C:11]([O:16][CH3:17])=[CH:12][C:13]=2[O:14][CH3:15])[CH2:6][CH2:5][N:4]([CH3:20])[CH2:3]1
Reactant: COc1cc(OC)c(C2=CCN(C)CC2O)c(OC)c1
Solvent: O
Product: COc1cc(OC)c([C@H]2CCN(C)C[C@H]2O)c(OC)c1

Procedure:
Disclosed is a method for producing (−)cis-3-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-piperidine characterized in that 1-methyl-piperidine-4-one is converted into hydrobromide, subsequently transformed with bromine into 3(R,S)-bromine-1-methyl-4-oxo-piperidine-hydrobromide and reacted with 1,3,5-trimethoxybenzol to form 3(R,S)-bromine-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydro-pyridine-hydrobromide. By stirring the reaction solution into an organic solvent, 3(R,S)-bromine-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydro-pyridine-hydrobromide is initially isolated as a solid and subsequently the product is mixed with water and converted into 3(R,S)-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydro-pyridine by means of stirring. The product thus prepared is catalytically hydrogenated into a racemic 3,4-cis-alcohol and subsequently, enantiomerically pure (−)cis-3-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-piperidine is obtained by separation of racemic mixtures with chiral auxiliary reagents from racemic 3,4-cis alcohol.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=1[OH:10].[CH2:11](OC(OCC)OCC)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>>[O:10]1[C:4]2[CH:5]=[C:6]([OH:7])[CH:8]=[CH:9][C:3]=2[N:2]=[CH:11]1
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccc(O)cc1O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: Oc1ccc2ncoc2c1

Procedure:
4-Aminoresorcinol hydrochloride (3.0 g, 18.5 mM), triethylorthoformate (9.1 g, 61.4 mM), and pyridinium-p-toluenesulfonate (PPTS, 250 mg, 1.0 mM) were refluxed in xylenes (200 mL) for about 18 hours. The reaction mixture was concentrated and the residue dissolved in ethyl acetate (200 mL) and washed with H2O (3×150 mL). The combined aqueous layer was back extracted with ethyl acetate (200 mL) and the combined organic layer was dried over MgSO4. Filtration and concentration provided an oil that was filtered through a silica gel column eluted with 1% methanol/methylene chloride to provide a brown solid, 1.66 g; m.p., 118-121° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]=[N+]=[N-])=[CH:4][C:3]=1[S:13](=[O:16])(=[O:15])[NH2:14].[ClH:17].C(O)(C)C>COCCOCCOC>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH2:9][Cl:17])=[CH:4][C:3]=1[S:13](=[O:16])(=[O:15])[NH2:14]
Reactant: Cc1ccc(C(=O)C=[N+]=[N-])cc1S(N)(=O)=O
Reactant: Cl
Solvent: COCCOCCOC
Solvent: CC(C)O
Product: Cc1ccc(C(=O)CCl)cc1S(N)(=O)=O

Procedure:
10 g of 4'-methyl-3'-sulfamoyl-diazoacetophenone were reacted as prescribed in Example 66(b) in diethylene glycol dimethyl ether with 37% HCl and worked up. Colorless crystals, melting point: 166° C. (from isopropanol).