Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2].[H-].[Na+].[Br:24][CH2:25][CH2:26][C:27]([CH3:32])([CH3:31])[CH2:28][CH2:29]Br.[Cl-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:29][CH2:28][C:27]([CH3:32])([CH3:31])[CH2:26][CH2:25][Br:24])[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2]
Reactant: CC(C)(CCBr)CCBr
Reactant: CCOC(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCC(C)(C)CCBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 24 g. of 5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester in 480 ml. of dimethylformamide is treated under argon at -10° C. with 0.16 mol. of sodium hydride (7.0 g of a 55% dispersion in mineral oil) and then stirred in an ice-bath for 15 minutes. To this, 62 g. of 1,5-dibromo-3,3-dimethylpentane are added in one batch at -5° C., the mixture is then stirred for 1 hour at room temperature and subsequently heated for 18 hours at 60° C. After cooling, the mixture is poured into 4 liters of ice-water, 200 g. of sodium chloride are added, and the separated product is immediately extracted with methylene chloride. The organic phase, shielded from daylight, is washed with a saturated solution of sodium chloride, dried over sodium sulfate and concentrated to dryness under reduced pressure. The resulting oily residue is chromatographed on 1000 g. of silica gel with methylene chloride as the eluant, care being taken that the eluate is shielded from daylight. The homogeneous fractions are combined, evaporated, and the solid residue recrystallized from ethanol, and there is obtained 2-(5-bromo-3,3-dimethylpentyl)-5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester having a melting point of 87°-88° C.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:29])[CH2:14][CH:15]([NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16](=[O:19])[CH2:17][F:18])(C)(C)C>C(Cl)Cl>[C:21]([NH:20][CH:15]([C:16](=[O:19])[CH2:17][F:18])[CH2:14][C:13]([OH:29])=[O:12])(=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)CC(NC(=O)c1ccccc1)C(=O)CF
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC(NC(=O)c1ccccc1)C(=O)CF
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (TFA) (10 ml) was added to a stirred ice cold solution of above prepared 3-benzoylamino-5-fluoro-4-oxo-pentanoic acid tert-butyl ester (600 mg, 1.94 mmol) in dry DCM (10 ml). The mixture was stirred at 0° C. for 0.5 h then at r.t. for 0.5 h. The mixture was concentrated under reduced pressure and the residue redissolved in dry DCM. This process was repeated several times in order to remove excess TFA. The resulting gum was triturated with Et2O. Filtration of the resulting suspension yielded the title compound as finely divided white powder (333 mg, 68%): 1H NMR (DMSO) δ 12.6 (1H, br s), 8.8 (1H, br m), 7.85 (2H, m), 7.50 (3H, m), 4.90 (2H, m), 4.80 (1H, m), 2.80 (2H, m); 13C NMR (DMSO) δ 166.97, 133.72, 132.5, 128.70, 127.83, 52.64, 34.58; 19F NMR (DMSO) δ −226.66(m), −230.34(m), −232.24(m); Acc. Mass; Calc. 254.0828, Found 254.0793.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]3[S:23][CH:24]=[C:25]([S:27][C:28]4[CH:33]=[CH:32][N:31]=[C:30]([C:34]([O:36]C)=[O:35])[CH:29]=4)[N:26]=3)=[N:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[Cl-].[NH4+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]3[S:23][CH:24]=[C:25]([S:27][C:28]4[CH:33]=[CH:32][N:31]=[C:30]([C:34]([OH:36])=[O:35])[CH:29]=4)[N:26]=3)=[N:19][CH:20]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(Sc2csc(Nc3ccc(NC4CCN(C(=O)OC(C)(C)C)CC4)cn3)n2)ccn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Nc3nc(Sc4ccnc(C(=O)O)c4)cs3)nc2)CC1
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
Methyl 4-(2-(5-(1-(tert-butoxycarbonyl)piperidin-4-ylamino)pyridin-2-ylamino)thiazol-4-ylthio)picolinate (0.33 g, 0.608 mmol) in THF (5 mL) was treated with sodium hydroxide (1M, 2.4 mL, 2.4 mmol) at room temperature. The mixture was stirred for 30 minutes, then saturated ammonium chloride (20 mL) was added and the THF was evaporated. The solid was filtered to give the title material as a solid (0.32 g, 97%) which was used as is. LCMS (M+H)+: 529. HPLC ret. time (Condition A): 1.327 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@:12]([CH3:16])([C:13]([OH:15])=O)[CH2:11][O:10][C:9]1([CH3:18])[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:53][CH2:54][C:55]([C:57]1[CH:62]=[CH:61][C:60]([O:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[C:59]([C:72]([F:75])([F:74])[F:73])[CH:58]=1)=[O:56]>CCOC(C)=O.CN(C=O)C>[CH3:17][C:9]1([CH3:18])[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@@:12]([CH3:16])([C:13](=[O:15])[NH:53][CH2:54][C:55]([C:57]2[CH:62]=[CH:61][C:60]([O:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[C:59]([C:72]([F:73])([F:74])[F:75])[CH:58]=2)=[O:56])[CH2:11][O:10]1
Reactant: CCCCCCCCOc1ccc(C(=O)CN)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCCCCCCOc1ccc(C(=O)CNC(=O)[C@@]2(C)COC(C)(C)N2C(=O)OC(C)(C)C)cc1C(F)(F)F
Yield: 40 %

Procedure:
To a solution of protected oxazolidine-4-carboxylic acid 4 (176 mg, 1 equivalents), HATU (310 mg, 1.2 equivalents), and DIEA (1.2 mL, 10 equivalents) in CH2CL2/DMF (1:1, 10 mL) was added amino-acetophenone 3 (250 mg, 1.0 equivalents). The resultant mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (50 mL) and washed with 10% NH4Cl (2×50 mL) and saturated NaCl (1×50 mL). The solvent removed in vacuo and the product was obtained, silica gel column chromatography using the Combi-Flash system (Hex:EtOAc), as a white solid in 40% yield (185 mg). TLC (1:2 EtOAc:Hex), Rf=0.3; MS (ESI, M+Na)=572.99; 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 8.11 (d, 1H, J=8.4 Hz), 7.05 (d, 1H, J=8.4 Hz), 4.62-4.79 (m, 2H), 4.13 (t, 2H, J=6.4 Hz), 3.28 (br s, 1H), 1.22-1.90 (m, 30H), 0.89 (t, 3H, J=6.4 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[N:6][CH:7]=1.[Li]CCCC.[Br:22][C:23]1[CH:24]=[CH:25][C:26]([Cl:31])=[C:27]([CH:30]=1)[CH:28]=[O:29]>C1COCC1.CCCCCC>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([Cl:31])=[C:27]([CH:28]([C:2]2[CH:7]=[N:6][C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=3[F:16])=[CH:4][CH:3]=2)[OH:29])[CH:30]=1
Reactant: Fc1ccc(Nc2ccc(Br)cn2)c(F)c1
Reactant: O=Cc1cc(Br)ccc1Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1ccc(Nc2ccc(F)cc2F)nc1)c1cc(Br)ccc1Cl
Reaction time: 0.33 h

Procedure:
(5-Bromo-pyridin-2-yl)-(2,4-difluoro-phenyl)-amine (3 g; 10.5 mmol) is dissolved in THF (70 ml) and cooled to −78 C. nBuLi (14.5 ml of a 1.5M solution in hexane; 23 mmol) is added dropwise and the resulting yellow suspension stirred or 20 min. 5-Bromo-2-chlorobenzaldehyde in THF (6 ml) is added at −78 C. After 5 min at −78 C, the reaction mixture is warmed to −50 C, poured on water and extracted with TBME twice. The combined organic phases are dried over Na2SO4 and evaporated to dryness. Purification via chromatography (SiO2; acetone/hexanes 6/94>12/88) yields the title compound as orange viscuous oil, (2.58 g; 58%) which is used in the next step. b) (5-Bromo-2-chloro-phenyl)-[6-(2,4-difluoro-phenylamino)-pyridin-3-yl]-methanone
Reaction SMILES: [NH3:1].[CH2:2]([N:9]1[CH2:13][CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[CH2:2]([N:9]1[CH2:13][CH2:12][C@@H:11]([NH2:1])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)O[C@H]1CCN(Cc2ccccc2)C1
Reactant: N
Solvent: CO
Product: N[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 67 %

Procedure:
An autoclave was cooled with an acetone/dry ice bath, and an ammonia gas was blown to pool 64 cc of liquid ammonia (corresponding to 25 equivalent of (S)-1-benzyl-3-(methanesulfonyloxy)pyrrolidine). Thereto were added 30 g of (S)-1-benzyl-3-(methanesulfonyloxy)pyrrolidine (108.4 mmol, optical purity: 100% e.e.) and 118 g of methanol, which was heated to 100° C. whereby an internal pressure of 10 barr was observed. After allowing the reaction for 7 hrs, the reaction mixture was cooled to room temperature, and ammonia and methanol were removed by distillation under reduced pressure. As the residue, 26.6 g of a pale yellow oily material was obtained (reaction yield: 67%, optical purity: 85.8% e.e.).
Reaction SMILES: C(OC[N:10]1[CH:14]=[C:13]([C:15]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][C:24]([O:32][CH3:33])=[C:25]([O:30][CH3:31])[CH:26]=3)[CH:21]=2)([OH:19])[CH:16]([CH3:18])[CH3:17])[N:12]=[CH:11]1)C1C=CC=CC=1.C(O)(=O)C>CO.[Pd]>[CH3:31][O:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:32][CH3:33])[CH:21]=[C:20]([C@@:15]([C:13]1[N:12]=[CH:11][NH:10][CH:14]=1)([OH:19])[CH:16]([CH3:18])[CH3:17])[CH:29]=[CH:28]2
Reactant: COc1cc2ccc(C(O)(c3cn(COCc4ccccc4)cn3)C(C)C)cc2cc1OC
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc2ccc([C@](O)(c3c[nH]cn3)C(C)C)cc2cc1OC
Temperature: 40 °C
Reaction time: 9 h
Yield: 76.3 %

Procedure:
1-(1-benzyloxymethyl-1H-imidazol-4-yl)-1-(6,7-dimethoxy-2-naphthyl)-2-methyl-1-propanol (20 g) was dissolved in warm methanol (1 L). Acetic acid (10.24 mL) and 10% Pd—C (50% wet; 20 g) were added and the mixture was stirred vigorously at 40° C. for 9 h under hydrogen atmosphere at 4 atmospheric pressure. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (600 mL), washed with sodium bicarbonate solution and 1M sodium bisulfite solution. The water layer was extracted with ethyl acetate. The organic layers were combined and dried over Na2SO4, concentrated in vacuo. The residue was crystallized from ethyl acetate-diisopropyl ether to give the titled compound (11.15 g) as colorless crystals.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]3[CH:13]=[C:14]([C@@H:20]4[O:25][C@H:24]([CH2:26][O:27][P:28](=[O:39])([O:34]C(C)(C)C)[O:29]C(C)(C)C)[C@@H:23]([OH:40])[C@H:22]([OH:41])[C@H:21]4[OH:42])[CH:15]=[CH:16][C:17]=3[CH2:18][CH3:19])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1>CO>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]3[CH:13]=[C:14]([C@@H:20]4[O:25][C@H:24]([CH2:26][O:27][P:28](=[O:29])([OH:34])[OH:39])[C@@H:23]([OH:40])[C@H:22]([OH:41])[C@H:21]4[OH:42])[CH:15]=[CH:16][C:17]=3[CH2:18][CH3:19])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCc1ccc([C@@H]2O[C@H](COP(=O)(OC(C)(C)C)OC(C)(C)C)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc2c(c1)OCCO2
Solvent: CO
Product: CCc1ccc([C@@H]2O[C@H](COP(=O)(O)O)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc2c(c1)OCCO2
Temperature: 25 °C
Yield: 73.6 %

Procedure:
To the stirred solution of phosphoric acid di-tert-butyl ester (2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester (500 mg) in methanol (20 ml) was added amberlyst 15 ion exchange resin (250 mg) and refluxed for overnight. Reaction mixture was cooled to room temperature, filtered through celite bed and filtrate was concentrated to give 300 mg of phosphoric acid mono-{(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl}ester. The crude material was taken up for next reaction.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1C(O)=O.[N:12]([O-])=O.[Na+]>OS(O)(=O)=O>[NH2:12][C@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@H:3]1[CH2:2][OH:1]
Reactant: O=C(O)[C@H]1CCCC[C@H]1CO
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: N[C@H]1CCCC[C@H]1CO
Temperature: 2.5 °C

Procedure:
The hydrazide of (1S,2R)-2-hydroxymethyl-1-cyclohexanecarboxylic acid (0.5 gram) is reacted with a solution of 0.5 grams of sodium nitrite in 10 ml of 5% H2SO4. The reaction mixture is maintained for 1 hour at 0-5° C, followed extraction of the reaction mixture with ethyl acetate, followed by basification of the resulting aqueous solution with NaOH, extraction with methyl t-butyl ether, drying of the extracts over MgSO4, filtration, and the removal of solvent by rotary evaporation. The product (1S,2R)-1-amino-2-(hydroxymethyl)cyclohexane is isolated as a light yellow
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:22]3[CH:23]=[C:24]([O:29][CH3:30])[C:25]([O:27][CH3:28])=[CH:26][C:21]=3[C@H:20]3[C@H:15]([CH2:16][CH2:17][N:18]([CH3:31])[CH2:19]3)[N:14]=2)=[CH:9][CH:8]=1.[OH-].[Na+]>O1CCOCC1.N1C=CC=CC=1>[CH3:30][O:29][C:24]1[C:25]([O:27][CH3:28])=[CH:26][C:21]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][N:18]([CH3:31])[CH2:19]3)[N:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:8][CH:9]=3)[C:22]=2[CH:23]=1
Reactant: COc1cc2c(cc1OC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(NS(C)(=O)=O)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A solution of 0.6 ml methanesulphonyl chloride in 3 ml absolute dioxane is added dropwise to a solution of 2.1 g rac-cis-6-(4-aminophenyl)-8,9-dimethoxy-1,2,3,4,4a, 10b-hexahydro-2-methyl-benzo[c ][1,6]naphthyridine in 20 ml absolute pyridine, and the mixture is then stirred at 60° C. for a further 3 h. After cooling, the mixture is poured onto 100 ml of an ice/water mixture, rendered alkaline with dilute sodium hydroxide solution and extracted with n-butanol. After the n-butanol has been evaporated off, the residue which remains is extracted with methylene chloride and the organic phase is dried over sodium sulphate and then concentrated. 2.4 g of the title compound are obtained as the residue and are converted into the dihydrochloride with ethereal HCl, and the product is recrystallized from non-dried methanol. Yield: 2.3 g of the title compound as the dihydrochloride hydrate. M.p. 239°-240° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[C:26]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)=[O:27]>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][S:14]([C:11]2[CH:12]=[CH:13][C:8]([C:2]3([CH3:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]3)=[CH:9][CH:10]=2)(=[O:16])=[O:15])=[C:20]([C:26]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[O:27])[CH:21]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1cccnc1
Reactant: CC1(c2ccc(S(=O)(=O)Cl)cc2)CCOCC1
Product: CC1(c2ccc(S(=O)(=O)Nc3ccc(Cl)cc3C(=O)c3cccnc3)cc2)CCOCC1

Procedure:
The title compound was prepared by the reacting 4-(4-methyl-tetrahydro-pyran-4-yl)-benzenesulfonyl chloride with (2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone according to the general procedure described for the preparation of (N-aryl-benzenesulfonamides. MS: m/z 471 (M++1).
Reaction SMILES: Br.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[CH:6]=[CH:5][N:4]=1.Cl[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].ClCCl>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: Nc1nccc2ccc(O)cc12
Reactant: CC(C)(C)OC(=O)NCCCCl
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCOc1ccc2ccnc(N)c2c1
Temperature: 70 °C
Reaction time: 72 h

Procedure:
4.0 g (12.7 mmol) of 1-amino-7-hydroxyisoquinoline monohydrobromide was dissolved in 50 ml of DMF. 4.42 g (18.6 mmol) of t-butyl (3-chloropropyl)carbamate, 8.76 g (63.5 mmol) of potassium carbonate and 4.69 g (12.7 mmol) of tetrabutylammonium iodide were added to the obtained solution, and they were stirred at 70° C. for 3 days. After the treatment with dichloromethane as the extraction solvent in an ordinary manner, the crude product was obtained, which was then purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:42])[CH2:6][CH2:7][NH:8][C:9](=[O:41])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([C:24]2[CH:25]=[N:26][C:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)=[CH:28][CH:29]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:12]([F:40])[CH:11]=1>CO>[F:40][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[O:16][CH:17]([C:24]1[CH:25]=[N:26][C:27]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:34][CH:35]=2)=[CH:28][CH:29]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:9]([NH:8][CH2:7][CH2:6][C:5]([OH:42])=[O:4])=[O:41]
Reactant: CCCCCCC(Oc1ccc(C(=O)NCCC(=O)OC)cc1F)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCC(Oc1ccc(C(=O)NCCC(=O)O)cc1F)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Reaction time: 3 h
Yield: 65.3 %

Procedure:
Add sodium hydroxide (5.0N, 0.07 mL, 0.34 mmol) to 3-(3-fluoro-4-{1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-heptyloxy}-benzoylamino)-propionic acid methyl ester (0.038 g, 0.07 mmol) in methanol (0.5 mL) and stir for three hours. Acidify with 1.0 N HCl and extract desired compound with ethyl acetate three times. Dry organic fractions with Na2SO4, filter and concentrate under reduced pressure to provide 0.025 g (66%) of title compound. MS (ESI) m/z 547.2 (M++H).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH2:21][CH2:22][CH3:23])=[CH:5][C:6](OS(C(F)(F)F)(=O)=O)=[N:7][C:8]=1[S:9][CH2:10][C:11]#[N:12])#[N:2].[OH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)CC)C.O>O1CCOCC1>[NH2:2][C:1]1[C:3]2[C:8](=[N:7][C:6]([N:28]3[CH2:29][CH2:30][CH:25]([OH:24])[CH2:26][CH2:27]3)=[CH:5][C:4]=2[CH2:21][CH2:22][CH3:23])[S:9][C:10]=1[C:11]#[N:12]
Reactant: OC1CCNCC1
Reactant: CCCc1cc(OS(=O)(=O)C(F)(F)F)nc(SCC#N)c1C#N
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCc1cc(N2CCC(O)CC2)nc2sc(C#N)c(N)c12
Temperature: 100 °C
Yield: 89 %

Procedure:
Trifluoro-methanesulfonic acid 5-cyano-6-cyanomethylsulfanyl-4-propyl-pyridin-2-yl ester (1.10 g, 3.00 mmol) (see Example 1, Method B) and 4-hydroxypiperidine (310 mg, 3.00 mmol) was suspended in 2 mL of dioxane. Triethylamine (0.84 mL, 6.0 mmol) was added and the reaction mixture was heated in a SmithSynthesizer™ (Personal Chemistry) at 100° C. for 2 h. This reaction mixture was poured into water and the resulting solid was collected by filtration and air dried to provide 3-amino-6-(4-hydroxy-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carbonitrile (845 mg, 89%).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([O:12][CH2:13][C@H:14]1[O:18][C@@H:17]([N:19]2[CH:26]=[C:25]([F:27])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:16][C@@H:15]1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)=[O:11])=O)(C)(C)C>Cl.O1CCOCC1>[ClH:36].[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][O:28][C@@H:15]2[C@@H:14]([CH2:13][O:12][C:10](=[O:11])[CH2:9][NH2:8])[O:18][C@@H:17]([N:19]3[CH:26]=[C:25]([F:27])[C:23](=[O:24])[NH:22][C:20]3=[O:21])[CH2:16]2)=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OCc1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Product: NCC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OCc1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 93 %

Procedure:
In 3 ml of 4N-HCl-dioxane was dissolved 0.88 g of 5'--O--[N-(t-butoxycarbonyl)glycyl]-3'-O-(4-chlorobenzyl)- 2'-deoxy-5-fluorouridine obtained in Example 8 (A), and the solution was left to stand for 30 minutes at room temperature. The solvent was distilled off and the residue was placed on silica gel column and eluted with 4-6% methanol-chloroform, giving 0.36 g (45%) of 3'-O-(4-chlorobenzyl)-2'-deoxy-5-fluoro-5'-O-glycyluridine hydrochloride.
Reaction SMILES: [OH-].[Na+].[CH:3]([CH:6]([C@H:16]1[CH2:19][C@H:18](C2C=C([N+]([O-])=O)C=CC=2C([O-])=O)[CH2:17]1)[C:7]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[O:8][SiH3:9])([CH3:5])[CH3:4].CC(O)=[O:34]>O1CCOCC1>[CH:3]([CH:6]([C@H:16]1[CH2:17][C@H:18]([OH:34])[CH2:19]1)[C:7]([CH:10]([CH3:11])[CH3:12])([CH:13]([CH3:15])[CH3:14])[O:8][SiH3:9])([CH3:4])[CH3:5]
Reactant: CC(=O)O
Reactant: CC(C)C([C@H]1C[C@H](c2cc([N+](=O)[O-])ccc2C(=O)[O-])C1)C(O[SiH3])(C(C)C)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)C([C@H]1C[C@H](O)C1)C(O[SiH3])(C(C)C)C(C)C
Reaction time: 1 h

Procedure:
Aqueous NaOH (0.4 mol/L, 12 mL, 4.56 mmol) was added to a stirred solution of trans-3-(triisopropyl-siloxyethyl)cyclobutyl-4-nitrobenzoate (0.96 g, 2.28 mmol) in 18 mL 1,4-dioxane at ambient temperature. After 1 hr, AcOH was added drop by drop. After 5 min, the reaction mixture was concentrated by rotovap. The residue was partitioned between EtOAc (10 mL) and saturated NaHCO3 (2×10 mL). The organic phase was dried over MgSO4 and solvent evaporation gave light yellow oil (0.57 g, 92.3%, Rf=0.23 (Hexane: EtOAc=9:1)). 1H NMR (CDCl3, 300 MHz): δ 1.00-1.07 (m, 21H), 1.63-1.70 (m, 2H), 1.78 (bs, 1H), 1.99-2.10 (m, 4H), 2.24-2.38 (m, 1H), 3.61-3.65 (t, J=6.6, 2H), 4.35-4.44 (m, 1H). 13C NMR (CDCl3, 75 MHz): δ 12.23, 18.29, 24.24, 38.05, 39.37, 62.27, 66.82. MS (FAB): expected for C15H32O2Si (M+H)+ 273.50. Found 273.22456.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])[CH:10]=2)[NH:5][C:4]1=[O:31].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>C1COCC1>[CH3:32][N:33]1[CH2:34][CH2:35][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])[CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:41][CH:40]=2)[CH2:37][CH2:38]1
Reactant: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)C(=CO)C(=O)N3)c1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)C(=CNc2ccc(N4CCN(C)CC4)cc2)C(=O)N3)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-amide (as prepared in Example 1, 30 mg, 0.072 mmol) and THF (1 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (20.7 mg, 0.1082 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. The reaction mixture was concentrated in vacuo and purified via flash silica gel chromatography (5% MeOH/95% CHCl3) providing the title compound in 57% yield (24 mg, 0.0407 mmol).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9]([CH2:12][CH2:13][CH3:14])(=[O:11])=[O:10])[C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.CC(C)([O-])C.[K+].[CH2:28]([OH:31])[CH2:29][OH:30]>>[OH:30][CH2:29][CH2:28][O:31][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9]([CH2:12][CH2:13][CH3:14])(=[O:11])=[O:10])[C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1
Reactant: OCCO
Reactant: CCCS(=O)(=O)Nc1ncnc(Cl)c1-c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCS(=O)(=O)Nc1ncnc(OCCO)c1-c1ccc(C)cc1
Temperature: 100 °C
Reaction time: 168 h

Procedure:
n-Propanesulfonic acid (6-chloro-5-p-tolyl-pyrimidin-4-yl)-amide (489 mg) was added to a solution of potassium tert.-butoxide (900 mg) in ethylene glycol (10 ml). The solution was stirred at 100° C. for 7 days. The reaction mixture was then poured onto ice/water and extracted with ethyl acetate. The crude product was purified by chromatography over silicagel with DCM/MeOH=9/1 to give n-propanesulfonic acid [6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (390 mg) as a white powder. LC-MS: tR: 3.76, [M+H]+: 352.13.