Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C@H:5](O)[C@H:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:34]1[C:39](O)=[CH:38][CH:37]=[C:36]([CH3:41])[CH:35]=1.N(C(OCC)=O)=NC(OCC)=O.[C:54]([OH:61])(=[O:60])/[CH:55]=[CH:56]\[C:57]([OH:59])=[O:58]>C1C=CC=CC=1.ClCCl.CCOCC>[C:54]([OH:61])(=[O:60])/[CH:55]=[CH:56]\[C:57]([OH:59])=[O:58].[CH3:1][N:2]1[CH2:7][CH2:6][C@@H:5]([C:39]2[CH:38]=[CH:37][C:36]([CH3:41])=[CH:35][CH:34]=2)[C@H:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1
Reactant: Cc1ccc(O)cc1
Reactant: CN1CC[C@H](O)[C@H](c2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C(O)/C=C\C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc([C@@H]2CCN(C)C[C@H]2c2ccccc2)cc1
Temperature: 6 °C
Reaction time: 18 h

Procedure:
A mixture of 4.78 g of cis-1-methyl-3-phenyl-4-piperidinol of Example 22, 7.21 g of triphenylphosphine, 2.97 g of p-cresol and 125 ml of anhydrous benzene is cooled to 6° C. and a solution of 4.79 g of diethyl azodicarboxylate in 125 ml of benzene is added dropwise under nitrogen over a 90-minute period. The temperature is allowed to rise gradually so that at completion of the addition it is 22° C. After stirring for 18 hours at room temperature, the suspended solid is filtered off, washed with hexane, and the filtrate concentrated in vacuo to an oil. This material is triturated with 200 ml of hexane for 90 minutes, the liquid is decanted, and the solid triturated for a few minutes with another 200 ml of hexane. Concentration in vacuo of the hexane extracts affords an oil, which is dissolved in 250 ml of dichloromethane and extracted with 2 N HCl solution. The dichloromethane phase is washed successively with 10% aqueous NaOH solution, water, and saturated aqueous NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to a mixture of a solid and an oil. This mixture is triturated with hexane, filtered, and the filtrate is concentrated in vacuo to afford an oil. This oil is chromatographed on silica gel, using acetone and then 25% methanol/acetone as solvent. The fractions containing product are combined and concentrated in vacuo to an oil which is taken up in ether and filtered through a Celite pad. The filtrate affords an oil which is triturated with boiling hexane and filtered hot. The filtrate is cooled and the resultant precipitated solid is filtered off and the filtrate concentrated in vacuo to yield an oil. This oil is dissolved in 50 ml of ether and added dropwise to a solution of 1.36 g of maleic acid in 25 ml of ether. The resulting solid is filtered, washed with ether, and dried to afford crude salt, melting near 100° C. Recrystallization from ethyl acetate affords a solid of trans-1-methyl-3-phenyl-4-(4-tolyl)piperidine maleate, mp s 130°, 131°-132° C.
Reaction SMILES: [I:1][C:2]1[C:3]2[CH:4]=[CH:5][C:6]([CH3:13])=[N:7][C:8]=2[C:9](=O)[NH:10][CH:11]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:9]1[N:10]=[CH:11][C:2]([I:1])=[C:3]2[C:8]=1[N:7]=[C:6]([CH3:13])[CH:5]=[CH:4]2
Reactant: Cc1ccc2c(I)c[nH]c(=O)c2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc2c(I)cnc(Cl)c2n1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
5-Iodo-2-methyl-7H-[1,7]naphthyridin-8-one (14.2 g, 49.8 mmol) was suspended in phosphorus oxychloride (68 ml, 750 mmol) and stirred for 5 hours at 90° C. The reaction mixture was cooled to room temperature and evaporated to dryness. The residue was taken up in dichloromethane and extracted carefully with saturated NaHCO3-Solution. The aqueous layer was washed two times with dichloromethane. The organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (ethyl acetate/heptane 10:90->100:0 gradient). The desired compound was obtained as a light red solid (4.8 g, 32%), MS: m/e=305.0 (M+H+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=3[N+:13]([O-:21])=[N:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C(O[BH3-])(=O)C.[Na+].CO>ClCCl.C(O)(=O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]2[N+:13]([O-:21])=[N:12][C:11](=[O:22])[N:10]([CH2:9][CH2:8][N:5]3[CH2:4][CH2:3][CH:2]([NH:1][CH2:34][C:32]4[CH:31]=[CH:30][C:27]5[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=5[N:33]=4)[CH2:7][CH2:6]3)[C:15]=2[CH:16]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: NC1CCN(CCn2c(=O)n[n+]([O-])c3ccc(Cl)cc32)CC1
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: O=C1COc2ccc(CNC3CCN(CCn4c(=O)n[n+]([O-])c5ccc(Cl)cc54)CC3)nc2N1
Yield: 18.8 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-chloro-1,2,4-benzotriazin-3(4H)-one 1-oxide (Intermediate 205, 0.517 g) was reacted with 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (117 mg) and sodium acetoxyborohydride (340 mg) as described for Example 107. Chromatography on silica gel with 0-20% methanol in dichloromethane gave 60 mg of the title compound as acetic acid salt.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[K+].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.Br[C:42]1[CH:47]=[C:46]([CH3:48])[C:45]([NH2:49])=[C:44]([O:50][CH3:51])[CH:43]=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].C1(C)C=CC=CC=1>[CH3:51][O:50][C:44]1[CH:43]=[C:42]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH:47]=[C:46]([CH3:48])[C:45]=1[NH2:49]
Reactant: C1COCCN1
Reactant: COc1cc(Br)cc(C)c1N
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: COc1cc(N2CCOCC2)cc(C)c1N
Reaction time: 0.25 h
Yield: 29 %

Procedure:
Bis(dibenzylideneacetone)palladium (0.63 g) and (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (0.68 g) were added to dry toluene (100 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (3.70 g), morpholine (4.0 mL) and 4-bromo-2-methoxy-6-methyl-phenylamine (3.40 g) were added subsequently. The reaction mixture was heated to reflux for 16 hours under argon, cooled and filtered through silica (50 g). Sodium hydroxide (2 M, 200 mL) was added and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic phases were washed with brine (1×200 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to furnish 1.0 g (29% yield) of the title compound as a black oil. 1H NMR (500 MHz, DMSO-d6): 2.05 (s, 3H), 2.91 (t, 4H), 3.69 (t, 4H), 3.74 (s, 3H), 3.95 (s, 2H), 6.23 (d, 1H), 6.39 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[H-].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:12]2=[O:22])[CH2:23][CH2:24]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [H-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1ccccc1)CN2c1ccccc1

Procedure:
The title compound was prepared from 4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (J. Med. Chem. (1992), 35, 423–30) and benzylbromide in analogy of the procedure described for the synthesis of (rac,cis)-3-methyl-1-phenyl-8-(2-phenyl-cyclohexyl)-1,3,8-triaza-spiro[4.5]decan-4-one (Example 69) by using potassium bis(trimethylsilyl)amide as base instead of sodium hydride. 3-Benzyl-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester was obtained as colorless solid; MS (ISP): 322.6 [M-(CO2+isobutylene)]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:11][Si](CC)(CC)CC)[CH2:9]I)=[CH:4][C:3]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.C(OCC)(=O)C>C1COCC1.[Cl-].[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:9][O:11]2)=[CH:4][C:3]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: CC[Si](CC)(CC)O[C@@H](CI)c1ccc(F)c(NS(C)(=O)=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)Nc1cc([C@@H]2CO2)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
(R)—N-(2-Fluoro-5-(2-iodo-1-(triethylsilyloxy)ethyl)phenyl)methanesulfonamide (2.4190 g) was dissolved in dehydrated THF (40 mL), and added with 1 mol/L-TBAF-THF solution (10 mL; manufactured by Sigma-Aldrich Co.), followed by replacement with nitrogen and stirring at room temperature for 1 hour. The reaction solution was added to brine, and extraction was carried out once with ethyl acetate. The organic layer was washed once with water and dried over magnesium sulfate. After the solvent was evaporated under reduced pressure, the resulting residue was purified by column chromatography (“COLUMN-B”; n-hexane:ethyl acetate=71:29→50:50) to obtain the title compound (0.5995 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]1[CH3:18])=[N:7][N:6]=[CH:5]2.[B:19]1(B2OC(C)(C)C(C)(C)O2)[O:23]C(C)(C)C(C)(C)[O:20]1.C([O-])(=O)C.[K+]>CN(C=O)C.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]>[CH3:18][C@@H:13]1[N:12]([C:8]2[C:9]3[C:4](=[CH:3][C:2]([B:19]([OH:23])[OH:20])=[CH:11][CH:10]=3)[CH:5]=[N:6][N:7]=2)[CH2:17][CH2:16][O:15][CH2:14]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: C[C@H]1COCCN1c1nncc2cc(Br)ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H]1COCCN1c1nncc2cc(B(O)O)ccc12
Temperature: 85 °C
Reaction time: 18 h

Procedure:
A mixture of (S)-6-bromo-1-(3-methylmorpholino)phthalazine (1.60 g, 5.2 mmol), bis(pinacolato)diboron (2.0 g, 7.8 mmol) and potassium acetate (2.5 g, 26 mmol) in DMF (25 mL) was degassed with N2 for 20 min. It was then treated with 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (0.38 g, 0.52 mmol). The reaction mixture was stirred at 85° C. under nitrogen for 18 h. After cooling to ambient, the reaction mixture was diluted with ethyl acetate (50 mL, and filtered through a Celite® pad, and rinsed with additional ethyl acetate (2×10 mL). The filtrate was concentrated. The residue was treated with diethyl ether (50 mL) and 1 N aqueous HCl (50 mL), and then filtered through a Celite pad. The filtrate was transferred to a separatory funnel, the aqueous phase was separated, concentrated under vacuum and the brown residue was purified on a reversed phased HPLC (5-90% [0.1% TFA in acetonitrile] in [0.1% TFA in water]) to give (S)-1-(3-methylmorpholino)phthalazin-6-ylboronic acid as a light yellow amorphous solid. MS (ESI, pos.ion) m/z: 274.0 (M+1).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1.[CH3:41][NH:42][CH2:43][C:44]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47]([CH3:54])=[CH:46][CH:45]=1.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([N:42]([CH3:41])[CH2:43][C:44]2[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:47]([CH3:54])=[CH:46][CH:45]=2)=[O:13])=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1
Reactant: CN1CCN(Cc2cc(/C=C/C(=O)O)cnc2N)CC1
Reactant: CNCc1ccc(C)c2ccccc12
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: Cc1ccc(CN(C)C(=O)/C=C/c2cnc(N)c(CN3CCN(C)CC3)c2)c2ccccc12
Yield: 20 %

Procedure:
According to the procedure of Example 1, except substituting (E)-3-[6-amino-5-(4-methyl-piperazin-1-ylmethyl)pyridin-3-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting methyl-(4-methyl-naphthalen-1-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (143 mg, 20%) was prepared as a pale, yellow solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.35-8.29 (m, 2H), 8.18-8.05 (m, 4H), 7.65-7.52 (m, 3H), 7.41-7.03 (m, 3H), 5.30-5.07 (m, 2H), 3.63-3.33 (m, 6H), 3.04-2.95 (m, 7H), 2.72-2.65 (m, 6H); MS (ESI) nm/e 444 (M+H)+.
Reaction SMILES: C[Al](C)C.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11].[Si:12]([O:29][CH2:30][CH:31]1[CH2:34][N:33]([CH2:35][C@H:36]([OH:41])[C:37](OC)=[O:38])[CH2:32]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Si:12]([O:29][CH2:30][CH:31]1[CH2:34][N:33]([CH2:35][C@H:36]([OH:41])[C:37]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=2)=[O:38])[CH2:32]1)([C:25]([CH3:26])([CH3:28])[CH3:27])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)[C@@H](O)CN1CC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Reactant: Nc1ccccn1
Agent: C[Al](C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCC1CN(C[C@H](O)C(=O)Nc2ccccn2)C1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 59.4 %

Procedure:
Trimethylaluminium (1.344 mL, 2.69 mmol) was added to pyridin-2-amine (220 mg, 2.34 mmol) in toluene (20 mL) cooled to 0° C. under nitrogen over a period of 10 minutes. The resulting solution was stirred at 0° C. for 10 minutes. (S)-Methyl 3-(3-((tert-butyldiphenylsilyloxy)methyl)azetidin-1-yl)-2-hydroxypropanoate (Intermediate BG2) (1.43 g, 2.34 mmol) in toluene (5 mL) was added over 10 minutes and the reaction was allowed to warm to room temperature and then heated at 110° C. for 2 hours. The reaction mixture was cooled and poured into a 20% solution of Rochelle salt (30 mL), diluted with ethyl acetate (80 mL) and stirred for 1 hour. The organic phase was separated, washed with water and brine, dried over MgSO4 filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% (10% MeOH in DCM) in DCM to afford the product (681 mg, 59.5%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[N:6]=1)=[O:4].[F:19][B-](F)(F)F.F[B-](F)(F)F.Cl[N+]12CC[N+](F)(CC1)CC2C.C(OCC)C.Cl>C(#N)C.O>[CH3:1][O:2][C:3]([C:5]1[C:9]([F:19])=[C:8]([O:10][CH3:11])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[N:6]=1)=[O:4]
Reactant: F[B-](F)(F)F
Reactant: COC(=O)c1cc(OC)n(-c2ccccc2F)n1
Agent: CC1C[N+]2(F)CC[N+]1(Cl)CC2
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Solvent: O
Product: COC(=O)c1nn(-c2ccccc2F)c(OC)c1F
Reaction time: 8 h
Yield: 32.6 %

Procedure:
200 mg (0.8 mmol) of 1-(2-fluoro-phenyl)-5-methoxy-1H-pyrazole-3-carboxylic acid methyl ester were dissolved in 2 ml of acetonitrile and 745 mg (1.99 mmol) of 1-chloro-methyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor®) were added. The mixture was stirred overnight. Then, irrespective of the incomplete reaction, diethyl ether, water and 2 N hydrochloric acid were added, the organic phase was separated, the solvent evaporated and the residue subjected to preparative HPLC. 70 mg (33%) of the title compound were obtained.
Reaction SMILES: [Mg].II.[CH2:4](Br)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][Cl:23].S(=O)(=O)(O)O>C1COCC1.[Cu](I)I>[CH2:22]([Cl:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=[CH2:4]
Reactant: ClCCCCCCBr
Reactant: C=CCCCCCCCCCBr
Agent: I[Cu]I
Agent: II
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: C=CCCCCCCCCCCCCCCCCl
Reaction time: 0.5 h
Yield: 25.3 %

Procedure:
This example illustrates a synthesis of 1-(16,17-Oxidoheptadecyl)-3,7-dimethylxanthine (inventive compound no. 3516). To a suspension of magnesium (3.10 g, 129 mmol) and a crystal of iodine in THF (10 mL) was added 10-undecenyl bromide (6.00 g, 25.8 mmol, available from MTM) in THF (20 mL) over 40 minutes and the reaction stirred for a further 30 minutes after the addition was complete. The solution was added via a canula over 50 minutes to a suspension of copper iodide (0.50 g, 2.58 mmol) and 1-bromo-6-chloro hexane (6.00 mL, 40.0 mmol) in THF (20 mL) and stirred at 25° C. for 16 hours. Sulfuric acid (1.0M, 50 mL) was added, extracted with diethyl ether (2×60 mL) and the organic solvent dried using magnesium sulfate and the solvent subsequently evaporated. The residue was distilled at 0.75 mmHg to yield 1.78 g (25% yield, b.p. 130°-135° C.) 16-heptadecenyl chloride as a colourless liquid.
Reaction SMILES: B.C1CN[C@H](C(O)(C2C=CC=CC=2)C2C=CC=CC=2)C1.[N:21]1([CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([C:39]3[C:48]4[C:43](=[CH:44][C:45]([OH:49])=[CH:46][CH:47]=4)[CH:42]=[CH:41][C:40]=3[C:50]3[C:55]([F:56])=[CH:54][C:53]([F:57])=[CH:52][C:51]=3[F:58])=[O:38])=[CH:33][CH:32]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(CN)O>C1COCC1.[Cl-].[Na+].O>[N:21]1([CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([CH:37]([OH:38])[C:39]3[C:40]([C:50]4[C:55]([F:56])=[CH:54][C:53]([F:57])=[CH:52][C:51]=4[F:58])=[CH:41][CH:42]=[C:43]4[C:48]=3[CH:47]=[CH:46][C:45]([OH:49])=[CH:44]4)=[CH:33][CH:32]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(c1ccc(OCCN2CCCCCC2)cc1)c1c(-c2c(F)cc(F)cc2F)ccc2cc(O)ccc12
Agent: B
Agent: OC(c1ccccc1)(c1ccccc1)[C@@H]1CCCN1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: NCCO
Product: Oc1ccc2c(C(O)c3ccc(OCCN4CCCCCC4)cc3)c(-c3c(F)cc(F)cc3F)ccc2c1
Temperature: 45 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
Charge a flask with 1M borane in THF (4 mL) and (R)-(+) α,α-diphenylprolinol (26 mg, 0.1 mmol). Dissolve [4-(2-azepan-1-yl-ethoxy)-phenyl]-[6-hydroxy-2-(2,4,6-trifluoro-phenyl)-naphthalen-1-yl]-methanone (348 mg, 0.7 mmol) in THF (3 mL) and add to the catalyst solution via syringe pump over 1.5 hours at 45° C. Upon completion of the reaction add ethanolamine (0.8 mL, 13.4 mmol) and heat at 45° C. for 2 hours. Cool the reaction to room temperature and add brine (5 mL) and stir for 1 hour. Filter the reaction and separate layers. Dry the organic layer with sodium sulfate, filter and concentrate in vacuo. Purify by silica gel chromatography using a 1.5-5% gradient of methanol in dichloromethane to yield 306 mg (88%) of the title compound: mass spectrum (ion spray) m/z=522 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH3:20])[NH:10][C:9]1=[N:21][NH2:22])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]([F:33])([F:32])[C:26]1([C:29](O)=O)[CH2:28][CH2:27]1.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.C(=O)(O)[O-].C(O)(=O)C>ClCCl.C(#N)C>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@@H:11]([CH3:20])[N:10]2[C:29]([C:26]3([C:25]([F:33])([F:32])[F:24])[CH2:28][CH2:27]3)=[N:22][N:21]=[C:9]12)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: C[C@H]1NC(=NN)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: CC#N
Solvent: ClCCl
Product: C[C@@H]1[C@H](c2ccccc2)C[C@H](NC(=O)OC(C)(C)C)c2nnc(C3(C(F)(F)F)CC3)n21
Reaction time: 1 h

Procedure:
To a solution of crude tert-butyl[(3S,5S,6R)-2-hydrazinylidene-6-methyl-5-phenylpiperidin-3-yl]carbamate (99 mg, 0.31 mmol) in dichloromethane (3.1 mL) was added 1-(trifluoromethyl)cyclopropanecarboxylic acid (58 mg, 0.37 mmol), 1-hydroxy-7-azabenzotriazole (4.3 mg, 0.031 mmol), N-methylmorpholine (82 μL, 0.75 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72 mg, 0.37 mmol). The mixture was stirred 1 h. Saturated aqueous bicarbonate was added, and the resulting mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Acetonitrile (12.5 mL) and glacial acetic acid (18 μL, 0.31 mmol) were added and the resulting mixture stirred at 70° C. for 90 min. Saturated aqueous bicarbonate was added, and the resulting mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated giving the crude title compound. MS 437.2 (M+1).
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][C:44]([CH3:75])([CH2:68][N:69]1[CH2:74][CH2:73][O:72][CH2:71][CH2:70]1)[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][C:52]=2[N:58]([CH3:67])[S:59]([C:62]1[S:63][CH:64]=[CH:65][CH:66]=1)(=[O:61])=[O:60])=O)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:67][N:58]([C:52]1[CH:53]=[CH:54][CH:55]=[C:56]2[C:51]=1[NH:50][C:49]([C:47]1[S:43][C:44]([CH3:75])([CH2:68][N:69]3[CH2:74][CH2:73][O:72][CH2:71][CH2:70]3)[CH2:45][N:46]=1)=[CH:57]2)[S:59]([C:62]1[S:63][CH:64]=[CH:65][CH:66]=1)(=[O:61])=[O:60]
Reactant: CN(c1cccc2cc(C(=O)NCC(C)(CN3CCOCC3)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Agent: O=C([O-])O
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: CN(c1cccc2cc(C3=NCC(C)(CN4CCOCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 0.17 h
Yield: 56.8 %

Procedure:
To a solution of triphenylphosphine oxide (1.00 g) in acetonitrile (20 ml) was slowly added trifluoromethanesulfonic anhydride (0.30 ml) at 0° C., and the mixture was stirred for 10 min. N-[2-(Benzylthio)-2-methyl-3-(morpholino)propyl]-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (0.43 g) was added, and the reaction mixture was stirred at 0° C. for 30 min. Saturated aqueous sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (0.20 g, yield 57%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). melting point 146-147° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=2)[N:3]=1.[Br-].[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[Zn+]>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].C1COCC1>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=2)[N:3]=[C:2]([C:21]2[S:20][CH:24]=[CH:23][N:22]=2)[CH:7]=1
Reactant: [Zn+]c1nccs1
Reactant: CC(C)Oc1ccc(-c2cc(Cl)cc(Cl)n2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2cc(Cl)cc(-c3nccs3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
To a dry 2 dram vial equipped with a stir bar was added 2,4-dichloro-6-(4-isopropoxyphenyl)pyridine (60 mg, 0.21 mmol) and Pd(dppf)Cl2 (8 mg, 10 μmol). The vial was sealed with a septum screw-cap and was then placed under N2 atmosphere. To the vial was added THF (0.5 mL), then thiazol-2-ylzinc(II) bromide in THF (0.5M, 0.53 mL, 0.27 mmol). The vial was placed in a 60° C. heating block with stirring for 2 hours. The vial was opened, and then charged with Pd(dppf)Cl2 (8 mg, 10 μmol). The vial was re-sealed and then placed under N2 atmosphere, and to the vial was added thiazol-2-ylzinc(II) bromide in THF (0.5M, 0.53 mL, 0.27 mmol). The vial was placed in a 60° C. heating block with stirring for 5 hours. The reaction solution was cooled to room temperature and then concentrated under a stream of N2. The resulting solid residue was subjected to silica gel chromatography to afford 2-(4-chloro-6-(4-isopropoxyphenyl)pyridin-2-yl)thiazole as a white solid (24 mg, 34%).