Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[C:11]2[S:10][C:9]([NH:12][C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.P(Br)(Br)[Br:29]>ClCCl>[Br:29][CH2:2][C:3]1[C:11]2[S:10][C:9]([NH:12][C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cc(C)c(Nc2nc3cccc(CO)c3s2)c(C)c1
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C)c(Nc2nc3cccc(CBr)c3s2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
To 0.065 g (0.22 mmol) of 7-(hydroxymethyl)-N-mesityl-1,3-benzothiazol-2-amine in 2 mL of dichloromethane was added 58 μL (0.72 mmol) of pyridine and 0.24 mL (0.24 mmol) of phosphorous tribromide (1 M in dichloromethane). The reaction was stirred at room temperature for 8 h and quenched with saturated sodium bicarbonate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give 0.045 g (57%) of the title compound that was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH2:15])=O)([O-:3])=[O:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>N1C=CC=CC=1.O1CCOCC1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]#[N:15])([O-:3])=[O:2]
Reactant: NC(=O)c1ccccc1Sc1ccccc1[N+](=O)[O-]
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: N#Cc1ccccc1Sc1ccccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 95.4 %

Procedure:
In a mixture of 12.7 g of pyridine and 80 ml of dioxane was suspended 8.8 g of 2-(2-nitrophenylthio)benzamide, followed by dropwise addition of 10.1 g of trifluoroacetic anhydride with ice-cooling, and the mixture was stirred for 1 hour. To the reaction mixture was added water and the crystals separated out therefrom were collected by filtration, washed with water and hot ethanol and dried. The procedure gave 7.84 g of the title compound as yellow crystals, m.p. 166°-167° C.
Reaction SMILES: CN(C)C=O.[C:6]([OH:16])(=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(Cl)([Cl:19])=O.Cl>>[C:6]([Cl:19])(=[O:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCC(=O)O
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCCCCCC(=O)Cl

Procedure:
100.5 g (1.38 mol) of N,N-dimethylformamide were added to 2.75 mol of pelargonic acid in a stirred apparatus. The reaction solution was brought to a temperature of from 20 to 30° C. with stirring, and a total of 2.78 mol of gaseous phosgene and simultaneously 1.92 mol of gaseous hydrogen chloride were introduced under atmospheric pressure. When the addition of phosgene and hydrogen chloride was complete, the two phases were separated from one another. The catalyst phase comprised a molar proportion of the catalyst adduct, based on the molar amount of N,N-dimethylformamide plus catalyst adduct, of 1%. The carbonyl chloride phase comprised 98.9% by weight of pelargonoyl chloride and 0.04% by weight of pelargonic anhydride. The color number was 18 APHA.
Reaction SMILES: [C:1]([CH2:9][C:10](=[O:17])CC(OCC)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:19][OH:20]>C(O)(=O)C>[C:2]1([C:1]2[NH:19][O:20][C:10](=[O:17])[CH:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: CCOC(=O)CC(=O)CC(=O)c1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: O=c1cc(-c2ccccc2)[nH]o1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
In accordance with the known process [Canadian Journal of Chemistry, 4s, 1371 (1970)], 154 g (0.8 mol) of ethyl benzoylacetoacetate were dissolved in 1 l of acetic acid, and 55.7 g (0.8 mol) of hydroxylamine hydrochloride were then added to the resulting solution, followed by heating under stirring at 100° C. for 5 hours. After the solvent was distilled off, ethyl alcohol was added to the residue to precipitate crystals. The crystals were collected and then washed with ethyl alcohol, whereby the title compound was obtained as colorless crystals.
Reaction SMILES: BrC1N=CC(C(N2CCN(C3C(C)=CC(C)=CN=3)CC2)=O)=CC=1.COC1C=CC(CN2C(=O)C(C)NC2=O)=CC=1.[CH3:41][C:42]1[C:43]([N:49]2[CH2:54][CH2:53][N:52]([C:55]([C:57]3[CH:58]=[CH:59][C:60]([N:63]4[CH:67]([CH3:68])[C:66](=[O:69])[N:65](CC5C=CC(OC)=CC=5)[C:64]4=[O:79])=[N:61][CH:62]=3)=[O:56])[CH2:51][CH2:50]2)=[N:44][CH:45]=[C:46]([CH3:48])[CH:47]=1>>[CH3:41][C:42]1[C:43]([N:49]2[CH2:50][CH2:51][N:52]([C:55]([C:57]3[CH:58]=[CH:59][C:60]([N:63]4[CH:67]([CH3:68])[C:66](=[O:69])[NH:65][C:64]4=[O:79])=[N:61][CH:62]=3)=[O:56])[CH2:53][CH2:54]2)=[N:44][CH:45]=[C:46]([CH3:48])[CH:47]=1
Reactant: COc1ccc(CN2C(=O)C(C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)cn3)C2=O)cc1
Agent: COc1ccc(CN2C(=O)NC(C)C2=O)cc1
Agent: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NC(=O)C4C)nc3)CC2)c(C)c1

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (300 mg) described in Preparation Example 127 and 3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione (225 mg) described in Preparation Example 51 and by the reaction and treatment in the same manner as in Example 508, the title compound (92 mg) was obtained via 1-{5-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}-3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]2)[CH:5]=[C:4]([I:16])[CH:3]=1.C(N(CC)CC)C.[O:24](C(OC(C)(C)C)=O)[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=O>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:10][CH2:11][C@H:12]([NH:15][C:25](=[O:24])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:13][CH2:14]2)[CH:5]=[C:4]([I:16])[CH:3]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: N[C@H]1CC[C@H](Nc2cc(I)cc(Cl)n2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2cc(I)cc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of Example 213a (7.00 g, 19.91 mmol) and triethylamine (3.61 mL, 25.9 mmol) in tetrahydrofuran (150 mL) was added BOC2O (5.08 mL, 21.90 mmol) at 0° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture was diluted with EtOAc and washed with brine and saturated sodium bicarbonate. The organic layer was dried over MgSO4, filtered, concentrated, and purified on a 150 g column using the ISCO Companion flash system eluting with hexane/EtOAc (8:2 to 6:4) to give 5.42 g of the title compound.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH2:29]>CCOCC>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH:29][C:13](=[O:15])/[CH:12]=[CH:11]/[CH2:10][CH2:9][C:8]#[C:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cccc(CN)c1
Reactant: O=C(O)/C=C/CCC#Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COc1cccc(CNC(=O)/C=C/CCC#Cc2ccccc2)c1

Procedure:
7-phenylhept-2E-en-6-ynoic acid (100 mg) was converted to the acid chloride as described in Example 2(a). The acid chloride was treated with triethylamine (73 ul) and 3-methoxybenzylamine (77 ul) in ether (2 ml). The product was recovered as described in Example 1 and purified by chromatography on silica, eluting with ether:hexane (1:1) to yield N-(3-methoxybenzyl)-7-phenylhept-2E-en-6-ynamide as a colourless solid, m.p. 96.3°-98.9°.
Reaction SMILES: C([O:3][C:4](=[O:44])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C.C1COCC1>[F:39][C:36]([F:37])([F:38])[C:34]1[CH:35]=[C:30]([C:27]2[CH:28]=[CH:29][C:24]([C:20]3[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]4[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:44])=[O:3])=[CH:10][CH:11]=4)[N:19]=3)=[CH:25][CH:26]=2)[CH:31]=[C:32]([C:40]([F:43])([F:41])[F:42])[CH:33]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4cc(C(F)(F)F)cc(C(F)(F)F)c4)cc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 55 °C

Procedure:
Under nitrogen, 2-(4-{2-[2-(3′,5′-bis-trifluoromethylbiphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy}-phenoxy)-2-methyl propionic acid ethyl ester (0.53 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was treated with 2.0 N NaOH (2.0 mL). The reaction mixture was stirred at 55° C. for 1 H and concentrated in vacuo. The resulting slurry was suspended in ethyl acetate, acidified to pH 1 with 1N HCl, and partitioned. The organic layer was washed with brine, dried (N2SO4), and concentrated in vacuo to yield of a white solid. Rf=0.1 in 6:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ8.08 (d, 2H), 8.01 (s, 2H), 7.83 (s, 1H), 7.62 (d, 2H), 6.88-6.76 (m, 4H), 4.17 (t, 2H), 2.98 (t, 2H), 2.40 (s, 3H), 1.52 (s, 6H); MS (EI) 594.2 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[CH:9].[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]1[N:23]=[C:22]([NH2:24])[N:21]=[C:20]2[C:16]=1[NH:17][CH:18]=[N:19]2.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]1[N:23]=[C:22]([NH2:24])[N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[CH:9]
Reactant: C#CCCCCCCBr
Reactant: Nc1nc(-c2cccs2)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCCCCCCn1cnc2c(-c3cccs3)nc(N)nc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.1 %

Procedure:
8-Bromo-1-octyne (2.0 g, 10.6 mmol) prepared in step 1) was added to a dehydrated dimethylformamide (25 mL) solution containing 6-(thien-2-yl)-2-amino purine (1.2 g, 5.5 mmol) and potassium carbonate (2.3 g, 16.5 mmol), followed by stirring at room temperature for 15 hours. The reaction solution was concentrated and was separated between ethyl acetate and water. The organic layer was washed with saturated brine, was dried over anhydrous sodium sulfate, and was purified by medium-pressure preparative column chromatography to yield 6-(thien-2-yl)-9-(7-octynyl)-2-amino purine (1.6 g, 4.9 mmol, 87%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:27])[N:3]=1.C1(P(C2C=CC=CC=2)CCCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:59][N:60](C)CCN(C)C.[C-]#N.[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:27][C:4]1[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[N:7]=[C:2]([C:59]#[N:60])[N:3]=1
Reactant: CN(C)CCN(C)C
Reactant: Cc1cnc(N2CCC(C3CCN(c4cc(C)nc(Cl)n4)CC3)CC2)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C-]#N
Solvent: Cc1ccccc1
Product: Cc1cnc(N2CCC(C3CCN(c4cc(C)nc(C#N)n4)CC3)CC2)cn1
Temperature: 140 °C

Procedure:
The 1-(2-chloro-6-methylpyrimidin-4-yl)-1′-(5-methylpyrazin-2-yl)-4,4′-bipiperidine (700 mg, 1.8 mmol) was placed in a pressure tube and anhydrous toluene (4 mL) added. To the stirred solution was added: palladium(II) acetate (41 mg, 0.18 mmol), 1,5-bis(dipenylphosphino)pentane (159 mg, 0.36 mmol), N,N,N′,N′-tetramethylethylenediamine (0.11 mL, 0.724 mmol), and potassium cyanide (235 mg, 3.62 mmol). The vessel was degassed with N2, sealed and heated at 140° C. for 16 hours. The mixture was allowed to cool to r.t., diluted with ethyl acetate (50 mL), washed with brine (10 mL×1), dried over magnesium sulfate, filtered and concentrated in vac. The residue was purified by chromatography on silica gel with 20% acetone: hexanes to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Br)[CH2:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:25][C:24](=[O:26])[N:23]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=2)[C:22]1=[S:35])=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[C@@:25]2([CH2:11][CH2:10][CH2:9][C@H:8]2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[C:24](=[O:26])[N:23]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=2)[C:22]1=[S:35])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: BrCCCC(Br)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=S
Product: CC(C)(C)OC(=O)N1C(=S)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CCC[C@H]2c1ccc(Br)cc1

Procedure:
Using the same procedure as in Example 1 starting from 1-bromo-4-(1,4-dibromobutyl)benzene (423 mg, 1.1 mmol) (Preparation 4) and 3-(3,5-dichlorophenyl)-4-oxo-2-thioxoimidazolidine-1-carboxylic acid tert-butyl ester (361 mg, 1 mmol) (Preparation 9), (5R*,6S*)-6-(4-bromophenyl)-3-(3,5-dichlorophenyl)-4-oxo-2-thioxo-1,3-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester was obtained (54 mg) as a white solid. 1H NMR (CDCl3): 7.49 (2H, d, J=8.4 Hz), 7.33 (1H, m), 7.09 (2H, d, J=8.4 Hz), 6.22 (2H, m), 4.17 (1H, dd, J1=13.2 Hz, J2=5.4 Hz), 2.35–2.6 (3H, m), 2–2.35 (3H, m), 1.69 (9H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[N:15]=[C:14]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][C:25]([O:27]C)=[O:26])[C:13]([C:29]([F:32])([F:31])[F:30])=[CH:12][N:11]=1.[OH-].[Li+:47]>O1CCCC1.CO.O>[C:42]([O:41][C:39]([N:36]1[CH2:37][CH2:38][N:33]([C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]3[N:15]=[C:14]([CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH2:24][C:25]([O-:27])=[O:26])[C:13]([C:29]([F:31])([F:32])[F:30])=[CH:12][N:11]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:34][CH2:35]1)=[O:40])([CH3:45])([CH3:44])[CH3:43].[Li+:47]
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2OC)ncc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(=O)[O-])n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of tert-butyl 4-(3-methoxy-4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I6) (0.360 g, 0.572 mmol) in tetrahydrofuran (17 mL), methanol (3 mL) and water (5 mL) was added lithium hydroxide (0.042 g, 1.77 mmol) and the resulting mixture was stirred at room temperature for 20 hours. The reaction volatiles were evaporated in vacuo and the resulting residue was diluted with ethyl acetate and saturated aqueous sodium hydrogen carbonate. The aqueous phase was extracted with ethyl acetate (3×20 mL) and the combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate (20 mL), dried (magnesium sulfate), filtered, evaporated in vacuo and dried to give the title compound (I7) (0.356 g, 100%) as a yellow foam; 1H NMR (300 MHz, CDCl3) δ 1.48 (s, 9H), 2.96-3.06 (m, 8H) 3.56-3.62 (m, 6H), 3.77 (s, 3H), 6.47-6.51 (m, 2H), 7.00-7.11 (m, 2H), 8.00 (brs, 2H) and 8.43 (s, 1H). LCMS Method B: rt 9.00 min; m/z 616.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:9]2)[CH:3]=1.[H-].[Na+].Cl[C:24]1[S:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=1.Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.O>[C:29]([C:26]1[S:25][C:24]([NH:1][C:2]2[N:7]=[CH:6][N:5]=[C:4]([N:8]3[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15](=[O:20])[C:16]([F:18])([F:17])[F:19])[CH2:9]3)[CH:3]=2)=[N:28][CH:27]=1)#[N:30]
Reactant: N#Cc1cnc(Cl)s1
Reactant: Nc1cc(N2CCCC(NC(=O)C(F)(F)F)C2)ncn1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cnc(Nc2cc(N3CCCC(NC(=O)C(F)(F)F)C3)ncn2)s1

Procedure:
N-[1-(6-aminopyrimidin-4-yl)piperidin-3-yl]-2,2,2-trifluoroacetamide 9-4 (0.26 g, 0.9 mmol), sodium hydride (0.144 g, 3.6 mmol) and 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (0.13 g, 0.9 mmol) were treated as in Scheme 4 above. When the reaction was complete it was quenched with 5 equivalents of concentrated HCl (370 μL). The solution was then diluted with ethyl acetate, water and some dilute NaHCO3. The aqueous layer was removed and the organic layer dried, filtered and evaporated to dryness under reduced pressure. Trituration with ethyl ether produced 9-5 as a solid, which was used without further purification in the next step.
Reaction SMILES: C(O[CH:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10]1)C1C=CC=CC=1.[CH2:28]([OH:30])C>[Pd]>[OH:30][CH2:28][CH:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([CH:21]3[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[CH:19][CH:20]=2)[CH2:10]1
Reactant: O=C1CCC(c2ccc(N3CC(OCc4ccccc4)OC3=O)cc2)CC1
Reactant: CCO
Agent: [Pd]
Product: O=C1CCC(c2ccc(N3CC(CO)OC3=O)cc2)CC1

Procedure:
4.9 g (12.9 mmol) of (RS)-5-benzyloxy-3-[4-(4-oxo-cyclohexyl)-phenyl]-oxazolidin-2-one were dissolved in 500 ml of ethanol while heating and, after adding 5% Pd/C, hydrogenated at room temperature. After separating the catalyst the solvent was distilled off and the oil obtained was chromatographed on a 30-fold amount of silica gel. The methylene chloride-ethyl acetate (1:4) eluates were pooled and the solvent was distilled off. 3.2 g of product were obtained from ethyl acetate/hexane. M.p.: 151.5°-152.5°.
Reaction SMILES: CSC.[CH3:4][C:5]([CH3:21])([C:11]1[CH:16]=[CH:15][C:14]([I:17])=[C:13]([O:18][CH2:19][CH3:20])[CH:12]=1)[C:6](OCC)=[O:7].CC(O)C>C(OCC)C>[CH2:19]([O:18][C:13]1[CH:12]=[C:11]([C:5]([CH3:21])([CH3:4])[CH2:6][OH:7])[CH:16]=[CH:15][C:14]=1[I:17])[CH3:20]
Reactant: CCOC(=O)C(C)(C)c1ccc(I)c(OCC)c1
Solvent: CCOCC
Solvent: CC(C)O
Solvent: CSC
Product: CCOc1cc(C(C)(C)CO)ccc1I
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.3 %

Procedure:
Boran dimethylsulfide (33 mL, 66 mmol, 2M in tetrahydrofuran) was added to a solution of ethyl dimethyl-(3-ethoxy-4-iodophenyl)acetate (4.83 g, 13.3 mmol) in ethyl ether (40 mL). The reaction was stirred at room temperature for 3 d and stirred for an additional hour with 2-propanol (10 mL) to quench the excess borane. The solution was partitioned between aqueous sodium bicarbonate and methylene chloride. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated to give 2-ethoxy-4-(2-hydroxy-1,1-dimethylethyl)iodobenzene (4.23 g, 99%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9](F)=[C:8]2[C:3]=1[CH:4]=[C:5]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])[N:6]=[CH:7]2.[F:21][C:22]([F:36])([F:35])[O:23]C1C=C2C(C=C(O)N=C2)=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.CCN(CC)CC>C(Cl)Cl>[F:21][C:22]([F:36])([F:35])[O:23][C:10]1[CH:9]=[C:8]2[C:3]([CH:4]=[C:5]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])[N:6]=[CH:7]2)=[CH:2][CH:11]=1
Reactant: O=S(=O)(Oc1cc2c(Cl)ccc(F)c2cn1)C(F)(F)F
Reactant: Oc1cc2ccc(OC(F)(F)F)cc2cn1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Oc1cc2ccc(OC(F)(F)F)cc2cn1)C(F)(F)F

Procedure:
By following the procedure for the preparation of trifluoromethanesulfonic acid 5-chloro-8-fluoroisoquinolin-3-yl ester, the title compound was prepared from 7-trifluoromethoxyisoquinolin-3-ol (0.98 g, 4.3 mmol), triflic anhydride (0.17 mL, 1.0 mmol), NEt3 (0.8 mL, 3.0 mmol) and CH2Cl2 (10 mL). 1H NMR (CDCl3, 300 MHz): δ=7.63 (s, 1H), 7.65 (d, J=6.0 Hz, 1H), 7.89 (s, 1H), 7.98 (d, J=9.0 Hz, 1H), 9.10 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[N:20][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CN(C)CCCOc1ccccc1C=O
Reactant: CCCCN
Solvent: Cc1ccccc1
Product: CCCCN=Cc1ccccc1OCCCN(C)C
Yield: 92.1 %

Procedure:
2-(3-Dimethylaminopropoxy)bezaldehyde (32.5 g) is reacted with 11.5 g of n-butylamine in 150 ml of toluene following the procedure described in Example 1, part A, to yield 37.9 g of oil product, boiling point 124°-128° C/0.1-0.2 mm of Hg.
Reaction SMILES: [N:1]([C:4]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:11]2[C:10](=[O:21])[N:9]([CH2:22][CH2:23][CH2:24][O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:8](=[O:32])[N:7]([CH3:33])[C:6]=2[N:5]=1)=[N+]=[N-].[H][H]>C1COCC1.[Pd]>[NH2:1][C:4]1[N:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[C:11]2[C:10](=[O:21])[N:9]([CH2:22][CH2:23][CH2:24][O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:8](=[O:32])[N:7]([CH3:33])[C:6]=2[N:5]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(N=[N+]=[N-])n2Cc1ccc(Cl)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(N)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.6 %

Procedure:
8-azido-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (0.19 g, 0.4 mmol) was dissolved in THF (5 mL) and 10% Pd/C (20 mg) was added. The reaction was blanketed in a hydrogen atmosphere (balloon) and stirred overnight at room temperature. The mixture was filtered through celite, the filter cake was washed with methanol. The filtrate was concentrated in vacuo to give a 8-amino-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (0.2 g, 100% yield) as a white solid. LCMS retention time 1.324 min; LCMS MH+-THP 364
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N+:23]=3[O-])=[CH:13][CH:12]=2)[CH2:5]1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Fe].C(O)(=O)C>[C:1]([N:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:15][CH:16]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC1(Cc2ccc(OCCCNc3cccc[n+]3[O-])cc2)CCCN(C(C)=O)C1
Agent: [Fe]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCOC(=O)CC1(Cc2ccc(OCCCNc3ccccn3)cc2)CCCN(C(C)=O)C1
Yield: 33.4 %

Procedure:
A mixture of the product from STEP 9 (335 mg), iron powder (74 mg, 1.3 mmol), triphenylphosphine (236 mg, 0.9 mmol), and acetic acid (6.3 ml) was heated at reflux for 30 min. The cooled reaction was filtered through a short column of Celite®, and washed with ethyl acetate. The filtrate was concentrated to give 108 mg of an colorless oil. This product mixture was used without further purification. The 1H NMR spectrum of the product was consistent for the proposed structure.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][CH:10]([CH3:12])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3]1.[O:14]1[CH:16]([CH2:17][CH3:18])[CH2:15]1>C(O)C>[OH:14][CH:16]([CH2:17][CH3:18])[CH2:15][N:3]1[CH:4]2[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:10]([CH3:12])[CH2:11][C:2]1([CH3:13])[CH3:1]
Reactant: CCC1CO1
Reactant: CC1CC(C)(C)NC2CCCCC12
Solvent: CCO
Product: CCC(O)CN1C2CCCCC2C(C)CC1(C)C

Procedure:
Following the procedures given above, 2,2,4-trimethyl decahydroquinoline of about 76% cis structure was reacted with 1,2-epoxybutane in the presence of ethanol to yield 58 grams of 1-(2'-hydroxybutyl)-2,2,4-trimethyl decahydroquinoline, which had a boiling point of 110° - 112° C. at 0.50 mm Hg. Calculated contents for the formula C16H31NO were 75.83% carbon, 12.33% hydrogen, and 5.53% nitrogen and the measured values were 76.55% carbon, 13.13% hydrogen, and 5.49% nitrogen.