Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][NH2:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([F:28])[C:23]=1[O:24][CH2:25][C:26]#[CH:27])[CH2:19]Cl.C(OCC)(=[O:31])C>>[CH:1]1([CH2:6][NH:7][C:19](=[O:31])[C:18]2[CH:17]=[C:16]([F:15])[C:23]([O:24][CH2:25][C:26]#[CH:27])=[C:22]([F:28])[CH:21]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC1CCCC1
Reactant: CCOC(C)=O
Reactant: C#CCOc1c(F)cc(CCl)cc1F
Solvent: CCN(CC)CC
Product: C#CCOc1c(F)cc(C(=O)NCC2CCCC2)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 0.50 g of cyclopentylmethylamine, 0.4 ml of triethylamine and 2 ml of ethyl acetate was added dropwise under ice cooling to a mixture of 3 ml of ethyl acetate and 0.46 g of 3,5-difluoro-4-(2-propynyloxy)benzyl chloride. The mixture obtained was stirred at room temperature for 12 hours. Then, the reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.24 g of N-cyclopentylmethyl-3,5-difluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 58 of the present invention) represented by the formula:
Reaction SMILES: [C:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1CCCCC1.CN(C)[CH:28]=[O:29]>O1CCCC1.C(OCC)(=O)C>[F:19][C:14]1[C:13]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:18][CH:17]=[CH:16][C:15]=1[CH:28]=[O:29]
Reactant: CCCCCCCCCCC#Cc1ccccc1F
Reactant: CN(C)C=O
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCC#Cc1cccc(C=O)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of 7.00 g (27.0 mmol) of 2-(1-dodecynyl)fluorobenzene in tetrahydrofuran (60 ml) at -78° C. was added slowly secobutyllithium (1.3M, cyclohexane) (21 ml). The mixture was stirred at -78° C. for 30 min, and dimethylformamide (2.8 ml) was added dropwise. The mixture was stirred for 5 min at -78° C. and allowed to warm to room temperature. The mixture was diluted with ethyl acetate and washed with water. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated in vacuo. The residue was flash chromatographed on silica gel (eluted with ethyl acetate/heptane/1:10). The appropriate fractions were collected and evaporated. The residue was chromatographed a second time over silica gel (eluted with dichloromethane) to afford 7.10 g (91%) of product.
Reaction SMILES: [Si:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[N:26]=[CH:25][C:24]4[NH:23][CH2:22][CH:21]5[CH2:27][O:28][CH2:29][CH2:30][N:20]5[C:19]=4[N:18]=3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](Cl)=[O:41])=[CH:35][CH:34]=1.C(N(CC)CC)C>C(Cl)Cl>[Si:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[N:26]=[CH:25][C:24]4[N:23]([C:40](=[O:41])[CH2:39][C:36]5[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=5)[CH2:22][CH:21]5[CH2:27][O:28][CH2:29][CH2:30][N:20]5[C:19]=4[N:18]=3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2c(-c3ncc4c(n3)N3CCOCC3CN4)cccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CC(=O)N2CC3COCCN3c3nc(-c4cccc5c4ccn5[Si](C)(C)C(C)(C)C)ncc32)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
2-(1-(tert-Butyldimethylsilyl)-1H-indol-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x12, 42 mg, 0.100 mmol) in CH2Cl2 (1 mL) was cooled to 0° C. 2-(4-Methoxyphenyl)acetyl chloride (0.018 mL, 0.120 mmol) was added, followed by triethylamine (0.028 mL, 0.199 mmol) to give a yellow solution. The reaction mixture was stirred for 2 hours at 0° C. The solvent was subsequently removed in vacuo and the resulting concentrate was loaded onto an ISCO® silica gel cartridge (4 g) and eluted using an ethyl acetatehexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a yellow oil (42 mg, 74%). 1H NMR (400 MHz, DMSO-d6) δ 0.64 (s, 6 H), 0.89 (s, 9 H), 3.02-3.22 (m, 4 H), 3.42-3.61 (m, 2 H), 3.66-3.78 (m, 3 H), 3.87-3.92 (m, 2 H), 3.91-3.98 (m, 1 H), 4.30-4.47 (m, 1 H), 4.64-4.75 (m, 1 H), 6.79-6.93 (m, 2 H), 7.00-7.30 (m, 3 H), 7.42-7.51 (m, 2 H), 7.61-7.68 (m, 1 H), 8.02-8.07 (m, 1 H), 8.32-9.02 (m, 1 H). ESI-MS m/z [M+H]+ calc'd for C32H39N5O3Si, 570.28; found 570.6.
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([NH:10][C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])[S:8][CH:9]=1)[C:3]#[N:4].N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].CCOCC>O>[C:25]([O:1][CH:2]([C:5]1[N:6]=[C:7]([NH:10][C:11]([O:13][CH2:14][C:15]([Cl:17])([Cl:18])[Cl:16])=[O:12])[S:8][CH:9]=1)[C:3]#[N:4])(=[O:27])[CH3:26]
Reactant: N#CC(O)c1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: O
Product: CC(=O)OC(C#N)c1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Reaction time: 1 h

Procedure:
To a solution of 1.10 g. of α-hydroxy-[2-(β,β,β-trichloroethoxycarbonyl)aminothiazol-4-yl]acetonitrile in 1 ml. of pyridine is added 2.5 ml. of acetic anhydride under ice-cooling and the mixture is stirred for 1 hour. To the mixture is added ether and water and the organic layer is washed with aq. NaHCO3 and further water in this order. Evaporation of ether gives α-acetoxy-[2-(β,β,β-trichloroethoxycarbonyl)aminothiazol-4-yl]acetonitrile. 1.3 g.
Reaction SMILES: Br.Br[CH:3]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=O.C(O)=O.C(N(CC)CC)C.[NH2:29][C:30](N)=[O:31]>C(#N)C>[F:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]2[N:29]=[CH:30][O:31][C:3]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:7][CH:8]=1
Reactant: NC(N)=O
Reactant: O=C(c1ccc(F)cc1)C(Br)c1ccncc1
Agent: Br
Solvent: O=CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Fc1ccc(-c2ncoc2-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-bromo-1-(4-fluoro-phenyl)-2-pyridin-4-yl-ethanone hydrobromide (10 g, Reference Example 9) in acetonitrile (100 ml) at 0° C. was treated with formic acid (10 ml) followed by triethylamine (35 ml). The solution was stirred at room temperature for 16 hours and urea (4 g) was added together with formic acid (100 ml). The resulting mixture was refluxed for 6 hours with concomitant removal of the acetonitrile [with a Mc Intire head]. The solvent was then evaporated, the residue taken up into ethyl acetate and the grey solid discarded. The solvent was evaporated and the resulting gum was dissolved in water (100 ml) and the solution basified to pH 11 by addition of sodium hydroxide pellets. The resulting solid was filtered and subjected to flash chromatography on silica eluting with ethyl acetate to give the title compound as a white solid. MS: 241 [MH+]. RF=0.34 (ethyl acetate, determined by thin layer chromatography on silica).
Reaction SMILES: [H-].[K+].[CH2:3]([CH:7]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[CH:18]=[C:8]1[CH2:9][N:10]2S(C1C(C)=CC=CC=1)(=O)=O)[CH2:4][CH2:5][CH3:6].O>NCCCN>[CH2:3]([CH:7]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[CH:18][C:8]1=[CH:9][NH:10]2)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCC1CCCCCCC2C=C1CN2S(=O)(=O)c1ccccc1C
Agent: NCCCN
Agent: [H-]
Agent: [K+]
Solvent: O
Product: CCCCC1CCCCCCc2cc1c[nH]2
Reaction time: 3 h

Procedure:
1,3-Diaminopropane (30 mL) is added to potassium hydride (10 mmol) under argon at room temperature. The mixture is stirred 3 hours. The resulting mixture is added dropwise at −15° C. over a period of an hour to a solution of the product of Example 8 (1 mmol) in 1,3-diaminopropane (15 mL). The resulting mixture is stirred at −15° C. for three hours and then is poured carefully into cold water. The aqueous phase is extracted with EtOAc, and the organic extracts are dried (Na2SO4), filtered and concentrated, affording a crude mixture of the above-titled compound. The crude mixture is purified using conventional chromatographic methods.
Reaction SMILES: [CH3:1][O:2][NH:3][CH:4]([CH3:15])[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[Cl:14].C(N(CC)CC)C.[F:23][CH:24]([F:34])[C:25]1[C:29]([C:30](Cl)=[O:31])=[CH:28][N:27]([CH3:33])[N:26]=1>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][N:3]([CH:4]([CH3:15])[CH2:5][C:6]1[C:7]([Cl:14])=[CH:8][C:9]([Cl:13])=[CH:10][C:11]=1[Cl:12])[C:30]([C:29]1[C:25]([CH:24]([F:34])[F:23])=[N:26][N:27]([CH3:33])[CH:28]=1)=[O:31]
Reactant: CONC(C)Cc1c(Cl)cc(Cl)cc1Cl
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
To a solution of O-methyl-N-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-hydroxylamine (12.3 g, 0.046 mol) prepared as described in example P5a in Xylene (90 g) was added triethylamine (5.6 g, 0.055 mol) followed by addition of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (40.1 g, 0.046 mol) at 70° C. during 2 hours. After complete addition of acid chloride the mixture was stirred 2 hours at 70° C. The solution was washed twice with water and the volatiles were removed from the organic layer under reduced pressure. The resulting crude mass 23.6 g (sticky dark brown oil) was purified by crystallization from a mixture of 16 g xylene and 36 g methylcyclohexene to give 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid methoxy-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-amide (17.0 g, 91.5%) as off white solid. m.p: 115-116° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11])#[CH:2].CCN(CC)CC.Cl[C:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([CH:39]3[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]3)=[C:35]([CH3:52])[CH:34]=2)[N:23]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:13][O:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:26]1[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([CH:39]3[CH2:40][CH2:41][N:42]([C:45]([O:47][C:48]([CH3:50])([CH3:49])[CH3:51])=[O:46])[CH2:43][CH2:44]3)=[C:35]([CH3:52])[CH:34]=2)[N:25]=1
Reactant: C#Cc1ccccc1CC(=O)OC
Reactant: Cc1cc(Nc2ncc(C(F)(F)F)c(Cl)n2)ccc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)c(C)c2)ncc1C(F)(F)F
Temperature: 120 °C

Procedure:
A solution of methyl 2-(2-ethynylphenyl)acetate (K1) (0.103 g, 0.589 mmol) in DMF (1.5 mL) and Et3N (0.273 mL, 1.96 mmol) were added to a suspension of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methylphenyl)piperidine-1-carboxylate (A40) (0.231 g, 0.491 mmol), PdCl2(PPh3)2 (0.052 g, 0.074 mmol), CuI (0.014 g, 0.074 mmol) and PPh3 (0.013 g, 0.049 mmol) in DMF (2 mL). The resulting mixture was heated under microwave irradiation at 120° C. for 15 minutes, then diluted with EtOAc and passed through a plug of Celite, washing with EtOAc (60 mL). The filtrate was washed with water (50 mL) and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organics were washed with water (50 mL), brine (50 mL) and dried (Na2SO4). The volatiles were removed in vacuo and the residue was purified by silica gel column chromatography (Biotage Isolera, 25 g SiO2 cartridge, 0-40% EtOAc in petroleum benzine 40-60° C.) to give the title compound A41 as a yellow oil (0.248 g, 83%); 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 7.68 (dd, J=7.6, 0.9 Hz, 1H), 7.47 (d, J=7.2 Hz, 1H), 7.45-7.40 (m, 1H), 7.39-7.29 (m, 4H), 7.18 (d, J=8.4 Hz, 1H), 4.38-4.21 (m, 2H), 3.96 (s, 2H), 3.70 (s, 3H), 2.92-2.71 (m, 3H), 2.38 (s, 3H), 1.75 (d, J=12.7 Hz, 2H), 1.69-1.54 (m, peak obscured), 1.49 (s, 9H). LCMS-A: rt 6.992 min; m/z 609.1 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=4)=[C:15](Br)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[N:55]1[CH:60]=[C:59](B(O)O)[CH:58]=[N:57][CH:56]=1>>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=4)=[C:15]([C:59]4[CH:60]=[N:55][CH:56]=[N:57][CH:58]=4)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C1C(Br)=C(c2cc(F)cc(F)c2)c2ccc(OCCN3CCOCC3)cc21
Reactant: OB(O)c1cncnc1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: O=C1C(c2cncnc2)=C(c2cc(F)cc(F)c2)c2ccc(OCCN3CCOCC3)cc21
Yield: 36 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 6-(2-morpholinoethoxy)-2-bromo-3-(3,5-difluorophenyl)-1H-inden-1-one obtained in Step 6 of Example 36 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 5-pyrimidinylboronic acid instead of 3-pyridinylboronic acid, and being purified by prep HPLC (CH3CN/H2O=7:3) to obtain the title compound (36%).
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[S:15](Cl)(=[O:17])=[O:16].[OH-].[Na+]>O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[S:15]([OH:17])=[O:16]
Reactant: Cc1ccc(Br)c(S(=O)(=O)Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(Br)c(S(=O)O)c1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 91.7 %

Procedure:
37.6 g of sodium sulfite are dissolved in 500 ml of water and heated to 70° C. 62 g of 2-bromo-5-methylbenzenesulfonyl chloride are added in portions at this temperature. A 10 N aqueous NaOH solution is simultaneously added dropwise here so that the pH of the solution is kept between pH=9 and pH=10. The mixture is stirred at 70° C. for 1.5 hours, and the solution is filtered off and subsequently adjusted to pH=0 in an ice bath using a saturated aqeuous HCl solution. The mixture is stirred for 30 minutes, then the product is filtered off, subsequently washed with a little water and dried. 49.6 g of white crystals are obtained,
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28]CC4C=CC(Cl)=CC=4Cl)[C@@H:14]([O:15]CC4C=CC(Cl)=CC=4Cl)[C@@:12]3([CH2:38][OH:39])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1>CO.ClCCl.[Pd]>[NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][OH:28])[C@@H:14]([OH:15])[C@@:12]3([CH2:38][OH:39])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1ccn2[C@@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@]1(O)CO
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Nc1ncnc2c1ccn2[C@@H]1O[C@H](CO)[C@@H](O)[C@]1(O)CO
Reaction time: 12 h
Yield: 84.4 %

Procedure:
The compound from Step B (120 mg, 0.2 mmol) was dissolved in 1:1 methanol/dichloromethane, 10% Pd-C was added, and the suspension stirred under an H2 atmosphere for 12 h. The catalyst was removed by filtration through a celite pad and washed with copious amounts of methanol. The combined filtrate was evaporated in vacuo and the residue was purified by flash chromatography (SiO2, 10% methanol in EtOAc containing 0.1% triethylamine) to give the title compound (50 mg) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]1[CH3:20].[BH4-].[Na+]>C(O)C>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:10][CH2:11][CH2:12][CH2:13][N:14]2[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]2[CH3:20])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cc1cn(CCCN)c(C)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cn(CCCNCc2ccc(Cl)cc2)c(C)n1
Product: Cl

Procedure:
In a similar manner to Example 35, a mixture of 4-chlorobenzaldehyde (3.8 g) and 1-(3-aminopropyl)-2,4-dimethylimidazole (4.1 g) in ethanol (70 ml) was stirred and then reduced with sodium borohydride (2.0 g). The hydrochloride salt was triturated with propan-2-ol, filtered and the residue washed with ether, then dried under vacuum at 45° C., to give N-(4-chlorobenzyl)-3-(2,4-dimethylimidazol-1-yl)propylamine dihydrochloride, m.p. 208°-210° C.
Reaction SMILES: C([O:5][C:6](=[O:57])[CH2:7][NH:8][C:9](=[O:56])[CH2:10][NH:11][C:12](=[O:55])[CH2:13][CH2:14][S:15][CH2:16][CH:17]([O:37][C:38](=[O:54])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:18][O:19][C:20](=[O:36])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])(C)(C)C.O1CC1C(O)C.FC(F)(F)C(O)=O>>[C:38]([O:37][CH:17]([CH2:18][O:19][C:20](=[O:36])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:16][S:15][CH2:14][CH2:13][C:12]([NH:11][CH2:10][C:9]([NH:8][CH2:7][C:6]([OH:57])=[O:5])=[O:56])=[O:55])(=[O:54])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)NCC(=O)NCC(=O)OC(C)(C)C)OC(=O)CCCCCCCCCCCCCCC
Agent: CC(O)C1CO1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)NCC(=O)NCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Yield: 100 %

Procedure:
To (6,7-bis(palmitoyloxy)-4-thiaheptanoyl)glycylglycine t-butyl ester as obtained in Example 3 (190 mg), trifiuoroacetic acid (2 ml) was added, followed by stirring at room temperature for I hour. The mixture was concentrated to yield the title compound (178 mg, yield 100%) as a colorless crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.I[CH2:27][C:28]#[N:29]>O1CCCC1>[C:28]([CH2:27][N:16]1[C:17]2[C:12](=[N:11][CH:10]=[C:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:18]=2)[C:13]([OH:25])=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]1=[O:19])#[N:29]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: N#CCI
Solvent: C1CCOC1
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC#N)c1=O
Yield: 101.8 %

Procedure:
In a similar manner to that described in example 316 step 1, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (29 mg, 0.085 mmol) lithium (bis-trimethylsilyl)amide (0.17 mL of a 1 M solution in tetrahydrofuran) and iodoacetonitrile (0.04 mL, 0.51 mmol) was prepared ethyl 1-(cyanomethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (33 mg, 95% yield) as a yellow oil. Product was carried on without further purification. 1H NMR (CDCl3) δ 8.51 (s, 1 H), 7.40 (s, 1 H), 7.15-7.09 (m, 2 H), 7.01-6.96 (m, 2 H), 5.10 (s, 2 H), 4.46 (m, 2 H), 4.13 (s, 2 H), 1.41 (m, 3 H); MS m/z 404 (M+23).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([CH:12](O)[CH3:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:39]I>CC#N>[C:1]([N:8]1[CH2:11][CH:10]([CH2:12][CH2:13][I:39])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: II
Reactant: CC(O)C1CN(C(=O)OC(C)(C)C)C1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(CCI)C1
Reaction time: 5 h
Yield: 83.7 %

Procedure:
A stirred solution of 133 (0.78 g, 3.8 mmol), PPh3 (1.1 g, 4.3 mmol), imidazole (0.40 g, 5.8 mmol), and CH3CN (20 mL) at 0° C. was treated with iodine (1.0 g, 4.3 mmol). After 15 min the cooling bath was removed and stirring continued for 5 h. The reaction mixture was then diluted with H2O and extracted with hexanes (5×25 mL then 4×50 mL). The combined extracts were dried (MgSO4) and concentrated. Flash chromatography (silica, 20% EtOAc/hexanes) gave 134 (0.99 g) as a colorless oil. Rf 0.44 (silica, 20% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3) δ 4.04 (t, J=7 Hz, 2H), 3.57 (dd, 2H), 3.10 (t, 2H), 2.64 (m, 1H), 2.16 (q, 2H), 1.43 (s, 9H). ##STR59##
Reaction SMILES: Br[CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:3].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1>>[CH3:3][CH:2]([O:18][C:14]1[CH:13]=[C:12]([O:11][CH3:10])[CH:17]=[CH:16][CH:15]=1)[CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)CCCC(C)Br
Reactant: COc1cccc(O)c1
Product: COc1cccc(OC(C)CCCC(C)C)c1

Procedure:
2-bromo-6-methyl-heptane was reacted with m-methoxy-phenol to obtain m-[(1,5-dimethyl-hexyl)-oxy]-anisole (boiling point = 210°-212°C/12 mmHg);
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]2[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:13]=2[N:14]=1
Reactant: CCc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCCc1ccccc1
Product: CCc1cc2c(NCCc3ccccc3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyrazin-2-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-phenethylamino-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[C:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[O:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)[C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[OH-].[Na+].Cl>CCO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[C:23]2[CH2:24][C:25]([CH3:32])([CH3:31])[O:26][C:27]([CH3:30])([CH3:29])[CH2:28]2)[C:10]2[CH:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCOC(=O)/C=C/c1ccc(C(=C2CC(C)(C)OC(C)(C)C2)c2ccc(O)c(Cl)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(/C=C/C(=O)O)cc2)c2ccc(O)c(Cl)c2)CC(C)(C)O1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of Ethyl(2E)-3-{4-[(3-chloro-4-hydroxyphenyl)(2,2,6,6-tetramethyl tetrahydro-4H-pyran-4-ylidene)methyl]phenyl}-2-propenoate (131) (0.32 g, 0.70 mmol) in a mixture of EtOH (6 mL) and THF (6 mL) was added an aqueous solution of 1 N NaOH (7 mL). The mixture was stirred at 60° C. for 2 h. Upon cooling, the mixture was acidified to pH=2 with an aqueous solution of 2 N HCl. The mixture was extracted with EtOAc (2×50 mL). The combined organic extract washed with brine and dried over Na2SO4. Upon concentration and adding hexanes, the title compound 132 was obtained as a white powder (0.255 g, 85%). mp 118-121° C. 1H NMR (400 MHz, DMSO-d6): δ 1.10 (s, 6H), 1.12 (s, 6H), 2.11 (s, 2H), 2.13 (s, 2H), 6.47 (d, J=15.9 Hz, 1H), 6.85-7.00 (m, 2H), 7.08 (d, J=1.8 Hz, 1H), 7.19 (d, J=8.2 Hz, 2H), 7.54 (d, J=15.9 Hz, 1H), 7.62 (d, J=8.2 Hz, 2H), 10.15 (s, 1H), 12.36 (s, 1H). LCMS (ESI): m/z 425 (M−H)−. Anal. Calcd for C25H27ClO4.0.2H2O: C, 69.74; H, 6.41; Found: C, 69.82; H, 6.56.