Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1C=CN=C1.CN1CCN(CCN(C)C)CC1.[CH3:19][N:20]([CH3:29])[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27]OC[CH2:24]1.C(N(C)C)CCCCCCCCCCCCCCCCC.C(N(C)C)CCCCCCCCCCCCCCC>>[CH3:24][N:23]1[CH2:22][CH2:21][N:20]([CH3:29])[CH2:19][CH:28]1[CH3:27]
Reactant: CN(C)CCN1CCOCC1
Agent: CCCCCCCCCCCCCCCCCCN(C)C
Agent: CCCCCCCCCCCCCCCCN(C)C
Agent: CN(C)CCN1CCN(C)CC1
Product: CC1CN(C)CCN1C

Procedure:
1-methylimidazole; N-methyl-4-(2 dimethylaminoethyl)piperazine; N,N,N-tris (dimethylaminopropyl) synhexahydrotriazine; N (2-dimethylaminoethyl) morpholine; octadecyl dimethylamine; hexadecyldimethylamine and the like.
Reaction SMILES: [CH:1]1([O:6][CH2:7][C:8]([O:10]CC)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[OH-].[K+]>O>[CH:1]1([O:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)COC1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)COC1CCCC1
Temperature: 25 °C

Procedure:
The product from Example 133A (2.56 g) was combined with MeOH (10 mL) and 40% aqueous KOH (8 mL) and water (8 mL) were added. The mixture was heated at reflux for 6 hours, and then cooled to room temperature. The mixture was concentrated under vacuum, and the residue was diluted with water (15 mL) and washed with hexanes (20 mL). The aqueous layer was cooled with ice and brought to pH<3 by addition of 10% HCl (30 mL). The resulting mixture was extracted with CH2Cl2 (3×20 mL). The combined extract was concentrated under vacuum to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.52-1.83 (m, 8H) 4.05 (s, 2H) 4.06-4.12 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].I[C:16]1[N:17]([CH3:27])[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:19][N:20]=1>>[CH3:8][C:7]1[O:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:1]#[C:2][C:16]1[N:17]([CH3:27])[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:19][N:20]=1
Reactant: Cn1c(-c2ccccc2)cnc1I
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: Cc1onc(-c2ccccc2)c1C#Cc1ncc(-c2ccccc2)n1C
Yield: 52 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted [using 2-iodo-1-methyl-5-phenyl-1H-imidazole (prepared from 1-methyl-5-phenyl-1H-imidazole according to J. Org. Chem. (43) 4381, 1978) instead of 2-chloro-4-iodopyridine] to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 88 mg, 52%) which was obtained as a light brown solid. MS: m/e=340.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].C([Sn]([C:24]1[O:25][CH:26]=[CH:27][CH:28]=1)(CCCC)CCCC)CCC.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CN(C=O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[C:24]1[O:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(F)c(-c2ccco2)c1
Temperature: 110 °C
Yield: 480.8 %

Procedure:
3-Bromo-4fluorobenzaldehyde (1 g, 4.93 mmol) in DMF (25 ml) was treated with 2 (tributylstannyl)furan (2.4 ml, 1.05 mmol), di-tert-butyl dicarbonate (1.75 g, 4.94 mmol), and tetrakis(triphenylphosphine)palladium (0) (570 mg, 0.4 mmol). The mixture was heated at 110° C. in a sealed high pressure tube over night, allowed to cool to ambient temperature, diluted with ethyl acetate, and washed with brine. The organic layer was further washed with 1N HCl, saturated NaHCO3, brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography using hexanes:diethyl ether (20:1) as eluent to provide the title compound as a pale yellow oil (0.96 g, 98%).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:29]([Cu])#[N:30]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:29]#[N:30])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2ccc(S(=O)(=O)c3ccccc3)cc2c1O
Reactant: N#C[Cu]
Product: CCCCOC(=O)c1nc(C#N)c2ccc(S(=O)(=O)c3ccccc3)cc2c1O
Yield: 49 %

Procedure:
Prepared from 6-benzenesulfonyl-1-bromo-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and CuCN in analogy to example 29a. Crude product was purified by silica gel chromatography (2%-20% ethyl acetate in methylene chloride) to give the title compound (49% yield). MS-(+)-ion: M+1=411.30.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH:11]=[O:12])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.Cl([O-])=[O:14].[Na+].P([O-])(O)(O)=O.[Na+]>CC(O)(C)C.CC(=CC)C.O>[O:1]1[C:10]2[CH:9]=[C:8]([C:11]([OH:14])=[O:12])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1cc2c(cn1)OCCO2
Temperature: 25 °C
Reaction time: 19 h
Yield: 51.2 %

Procedure:
To a solution of 2,3-dihydro-[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (722 mg, 4.37 mmol) in 2-methyl-2-propanol (95 mL) and 2-methyl-2-butene (22 mL) was added dropwise a solution of sodium chlorite (80%, 4.55 g, 40.22 mmol) and sodium dihydrogenphosphate (3.65 g, 26.45 mmol) in water (35 mL). The resulting solution was stirred at rt for 19 h. The volatiles were removed under reduced pressure. The residue was diluted with water (20 mL) and pH was adjusted to 3 by addition of 1N HCl. The aq. layer was extracted with DCM-MeOH 9-1 (25×30 mL). The combined extracts were dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was triturated in ether and filtered to give the title acid as a white solid (0.405 g, 51% yield).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH2:20]1>CS(C)=O>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH2:25][N:21]2[CH2:22][CH2:23][CH2:24][C@H:20]2[CH2:19][N:8]2[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=3[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]2=3)=[CH:32][CH:31]=1
Reactant: COc1ccc(CCN2CCC[C@@H](Cl)C2)cc1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CCN2CCC[C@H]2CN2c3ccccc3COc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 289.5 %

Procedure:
Sixty-percent sodium hydride (480 mg, 12 mmols) was washed with petroleum ether, and then suspended in 40 ml of dimethyl sulfoxide. To the suspension were added 2.0 g (10 mmols) of 5,11-dihydrodibenzo [b,e][1,4]oxazepine. The mixture was stirred in a nitrogen atmosphere at room temperature for 30 minutes. To this reaction solution was added dropwise a solution of 8.8 g (35 mmols) of (R)-(−)-3-chloro-1-(4-methoxyphenethyl)piperidine[[α]D25=−7.4 (c=1.1, ethanol)] in 30 ml of dimethyl sulfoxide at room temperature, and the mixed solution was stirred for 90 hours. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water and with a saturated aqueous solution of sodium chloride in this order, and dried. Subsequently, the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography, and eluted with a mixed solvent of ethyl acetate and hexane at a ratio of 1:2. This mixed solvent was distilled off under reduced pressure to give 12.0 g of (S)-(−)-5,11-dihydro-5-[1-(4-methoxyphenethyl)-2-pyrrolidinylmethyl]dibenzo[b,e][1,4]oxazepine as a pale yellow oil in a yield of 80%.
Reaction SMILES: [O:1]=[CH:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1.C[Si](C)(C)[C:23]([F:26])([F:25])[F:24].C1COCC1>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[F:24][C:23]([F:26])([F:25])[CH:2]([OH:1])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:7][CH2:6]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=CCOC1CCN(C(=O)OCc2ccccc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(OCC(O)C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
A mixture of benzyl 4-(2-oxoethoxy)piperidine-1-carboxylate (2.00 g), trimethyl(trifluoromethyl)silane (1.23 g), tetrabutylammonium fluoride (1 M THF solution, 1 drop) and THF (20 mL) was stirred at 0° C. for 1 hr, and then at room temperature for 3 days. Water was added thereto, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in THF (20 mL). Tetrabutylammonium fluoride (1 M THF solution, 8.65 mL) was added thereto at 0° C., and the obtained mixture was stirred at 0° C. for 2 hr. 1M Hydrochloric acid was added, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.60 g).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([OH:17])=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH3:29][N:30]1[CH2:34][CH2:33][C@@H:32](O)[CH2:31]1>C(Cl)(Cl)Cl>[CH3:29][N:30]1[CH2:34][CH2:33][C@@H:32]([O:16][C:15]([CH:13]2[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:6][C:7]3[C:12]2=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:17])[CH2:31]1
Reactant: O=C(O)C1c2ccccc2Oc2ccccc21
Reactant: CN1CC[C@@H](O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CN1CC[C@@H](OC(=O)C2c3ccccc3Oc3ccccc32)C1
Temperature: 0 °C
Yield: 92.9 %

Procedure:
2 g of 9H-Xanthene-9-carboxylic acid (0.0088 mol) were dissolved in 30 ml of CHCl3 (ethanol free). The solution was cooled at 0° C. and 1.08 ml (0.0123 mol) of oxalyl chloride and a drop of DMF was added. The mixture was stirred and allowed to warm to room temperature. After an hour at this temperature the solvents were evaporated and the residue was dissolved in CHCl3 and evaporated again. This procedure was repeated two times. The solid obtained (2.19 g) was dissolved in 20 ml of CHCl3 and added to a solution of 0.975 g (0.0097 mol) of (3R)-1-methylpyrrolidin-3-ol (Intermediate I-19) in 15 ml of CHCl3 cooled at 0–5° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated and the residue was dissolved in toluene and extracted with HCl 2N. The aqueous layer was basified with K2CO3 and extracted with CHCl3. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness to yield 2.53 g (93%) of the title product as an oil.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[S:11][CH:12]=2)[CH2:4][CH2:3]1.C(OC(Cl)=O)C>C1(C)C=CC=CC=1>[S:11]1[CH:12]=[C:8]([CH:5]2[CH2:4][CH2:3][NH:2][CH2:7][CH2:6]2)[C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]1=2
Reactant: CN1CCC(c2csc3ccccc23)CC1
Agent: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: c1ccc2c(C3CCNCC3)csc2c1
Reaction time: 20 h

Procedure:
11 g of 1-methyl-4-(benzo[b]thien-3-yl)-piperidine is dissolved in 120 ml of toluene. At a reaction temperature of 50°, 20 g of chloroformic acid ethyl ester is slowly added dropwise under a strong flow of nitrogen. The solution is thereupon stirred for 20 hours at 50°; a further 10 g of chloroformic acid ethyl ester is added dropwise and stirring is continued for 2 hours at 50°. The excess chloroformic acid ethyl ester is subsequently distilled off under normal pressure, the solution is cooled to 70°, filtered under suction and the filter residue is afterwards washed with 500 ml of toluene. The combined filtrates are successively washed with 500 ml of water, 800 ml of a 10% solution of methanesulphonic acid in water, 500 ml of water, 500 ml of 2N sodium hydroxide solution and 500 ml of water; they are dried with sodium sulphate, filtered and concentrated by evaporation. The resulting 4-benzo[b]thien-3-yl)-1-piperidinecarboxylic acid ethyl ester is dissolved in 110 ml of ethylene gylcol. After the addition of 13 g of solid sodium hydroxide, the formed cloudy solution is heated, with vigorous stirring, for 15 hours at 160°. The reaction solution is thereupon cooled to 20°, and extracted three times with 500 ml of ethyl acetate each time. The organic phases are washed 5 times with 1 litre of water each time, dried with sodium sulphate, filtered, combined, and concentrated by evaporation. The residue is dissolved in 500 ml of 2N hydrochloric acid and the acid solution is extracted with toluene. The aqueous solution is thereupon adjusted to have a pH-value of 12 by addition of 10% sodium hydroxide solution, and is then extracted with one litre of chloroform. The chloroform solution is dried with sodium sulphate, filtered and concentrated by evaporation; there is obtained crude 4-(benzo[b]thien-3-yl)-piperidine. The hydrochloride is prepared with hydrogen chloride in ethyl acetate and recrystallised from acetone, whereupon it melts above 270°.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:4]([F:14])=[C:5]([CH:9]=[C:10]([Cl:13])[C:11]=1[F:12])[C:6](F)=[O:7]>O>[Cl:2][C:3]1[C:4]([F:14])=[C:5]([CH:9]=[C:10]([Cl:13])[C:11]=1[F:12])[C:6]([NH2:1])=[O:7]
Reactant: N
Reactant: O=C(F)c1cc(Cl)c(F)c(Cl)c1F
Solvent: O
Product: NC(=O)c1cc(Cl)c(F)c(Cl)c1F
Reaction time: 0.5 h
Yield: 90 %

Procedure:
620 ml of concentrated aqueous ammonia solution and 600 ml of water are initially introduced, 458 g (2 moles) of 3,5-dichloro-2,4-difluorobenzoyl fluoride are added dropwise at 40°-50°, and then the mixture is stirred at 50° for 30 minutes. The precipitate is filtered off with suction, washed with water and dried. 408 g (90% of theory) of 3,5-dichloro-2,4-difluorobenzamide of melting point 163°-164° are obtained.
Reaction SMILES: [Br:1][C:2]1[CH2:3][CH:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:13])[CH:7]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:6][CH2:5]2.[N+:24]([O-])([O-:26])=[O:25].[NH4+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH2:3][CH:4]2[C:9](=[C:10]([N+:24]([O-:26])=[O:25])[CH:11]=1)[N:8]([C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:13])[CH:7]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:6][CH2:5]2
Reactant: CCOC(=O)C(=O)N1C2=CC=C(Br)CC2CCC1CC(=O)OC
Reactant: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCOC(=O)C(=O)N1C2=C([N+](=O)[O-])C=C(Br)CC2CCC1CC(=O)OC
Reaction time: 1.5 h
Yield: 106.7 %

Procedure:
To a refluxed solution of 6-bromo-2-methoxycarbonylmethyl-N-ethoxalyltetrahydroquinoline (40 g) and ammonium nitrate (8 g, 0.1 mol) in chloroform (100 mL) was added dropwise trifluoroacetic anhydride (56.5 mL, 0.4 mol) over 40 min. The reflux was continued for 90 min and crashed ice was added. The organic layer was separated, washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and concentrated to give 46 g of the title compound (quant): 1H NMR (270 MHz, CDCl3) δ8.11 and 7.99 (d and d, 1H, J=2 Hz), 7.66 and 7.61 (d and d, 1H, J=2 Hz), 5.03~5.16 and 4.74~4.85 (m and m, 1H), 4.37~4.49 and 4.13 (m and q, 2H, J=7.2 Hz), 3.72 and 3.62 (s and s, 3H), 2.44~3.02 (m, 5H), 1.65~1.80 and 1.50~1.60 (m and m, 1H), 1.42 and 1.23 (t and t, 3H, J=7.2 and 7.2 Hz).
Reaction SMILES: O=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C:4]2[N:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.O(Cl)[Cl:18].P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:18][C:2]1[C:3]2[CH:16]=[CH:15][CH:14]=[N:13][C:4]=2[S:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: ClOCl
Reactant: O=C1Nc2ccccc2Sc2ncccc21
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: ClC1=Nc2ccccc2Sc2ncccc21

Procedure:
40 G 5,6-DIHYDRO-5-OXOPYRIDO[2,3-B][1,5]BENZOTHIAZEPINE ARE ADDED TO A MIXTURE OF 200 CM3PHOSPHORUS OXYCHLORIDE AND 71 G PHOSPHORUS PENTACHLORIDE. The reaction mixture is heated under reflux for 4 hours, then the excess phosphorus oxychloride is eliminated by distillation. The residue is then taken up in 300 cm3 cold chloroform. The organic solution is washed several times with iced water, then dried over magnesium sulphate. The solvents are eliminated by distillation under vacuum at ambient temperature. The residue is taken up in anhydrous ether, then washed several times with cold ether. After drying under vacuum, 37 g 5-chloropyrido[2,3-b][1,5]benzothiazepine are obtained, having a melting point of 134°-135° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]([C:18]2C(C)=CC3C(C)(C)CCC(C)(C)C=3C=2)=[O:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[BH4-].[Na+]>CO>[CH3:1][C:2]1[C:3]([CH:16]([OH:17])[CH3:18])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1
Reactant: Cc1cc2c(cc1C(=O)c1cc3c(cc1C)C(C)(C)CCC3(C)C)C(C)(C)CCC2(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc2c(cc1C(C)O)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 4.17 g (17.1 mmol) of methyl [3,5,5,8,8-pentamethyl(5,6,7,8-tetrahydronaphthalen-2-yl] ketone (Compound 10) in methanol at 0° C. was portionwise added 0.77 g (20.4 mmol) of sodium borohydride and the resulting suspension stirred at 0° C. for 4 hours. Solvent was removed in-vacuo and the resulting :solid taken-up in water, acidified using 1N HCl, and extracted three times with ether. The ether extracts were washed with water, brine and dried (MgSO4). The solvent was removed in-vacuo and resulting residue purified using flash chromatography (SiO2, 10% ethyl acetate in hexanes) to give a single isomer: the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][NH:14][C:15]3[CH:33]=[CH:32][C:18]([C:19]([NH:21][C@H:22]([C:28]([O:30][CH3:31])=[O:29])[CH2:23][CH2:24][C:25](O)=[O:26])=[O:20])=[CH:17][CH:16]=3)[N:8]=2)[N:3]=1.C(N(CC)CC)C.[NH2:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54].[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C>CN(C)C=O.C(OCC)C>[NH2:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][NH:14][C:15]3[CH:33]=[CH:32][C:18]([C:19]([NH:21][C@H:22]([C:28]([O:30][CH3:31])=[O:29])[CH2:23][CH2:24][C:25](=[O:26])[NH:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][NH:50][C:51](=[O:57])[O:52][C:53]([CH3:55])([CH3:54])[CH3:56])=[O:20])=[CH:17][CH:16]=3)[N:8]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)NCCOCCOCCN
Reactant: COC(=O)[C@H](CCC(=O)O)NC(=O)c1ccc(NCc2cnc3nc(N)nc(O)c3n2)cc1
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCC(=O)NCCOCCOCCNC(=O)OC(C)(C)C)NC(=O)c1ccc(NCc2cnc3nc(N)nc(O)c3n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.9 %

Procedure:
To (S)-4-(4-((2-amino-4-hydroxypteridin-6-yl)methylamino)benzamido)-5-methoxy-5-oxopentanoic acid (240 mg, 0.53 mmol, crude), triethylamine (0.3 mL, 2.2 mmol), and tert-butyl 2-(2-(2-aminoethoxy)ethoxy)ethylcarbamate (150 mg, 0.60 mmol) in N,N-dimethylformamide (3 mL), 2-(2-pyridon-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (261 mg, 0.88 mmol) was added in one portion. The reaction was stirred at ambient temperature for 16 hours. After this time, the product was crashed out with diethyl ether and collected by suction filtration. The solids were washed with methylene chloride (30 mL) to afford crude (S)-methyl 18-(4-((2-amino-4-hydroxypteridin-6-yl)methylamino)benzamido)-2,2-dimethyl-4,15-dioxo-3,8,11-trioxa-5,14-diazanonadecan-19-oate (225 mg, 62%) as an orange-brown solid, which was used in the next step without further purification: MM-APCI MS m/z=684 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[N:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[S:20][C:8]=2[C:7]=1[OH:25])=[O:5])[CH3:2].[CH2:26](O)[CH3:27]>[Pd].C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:27][CH:26]=2)[C:9]2[N:18]=[C:19]([C:21]([CH3:23])([CH3:22])[CH3:24])[S:20][C:8]=2[C:7]=1[OH:25])=[O:5])[CH3:2]
Reactant: CCO
Reactant: CCOC(=O)c1nc(-c2ccccc2)c2nc(C(C)(C)C)sc2c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(CCc2ccccc2)c2nc(C(C)(C)C)sc2c1O
Reaction time: 4 h

Procedure:
A suspension of 2-tert-butyl-7-hydroxy-4-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (120 mg, 0.31 mmol) and 75 mg of 10% palladium on carbon in 6 mL of 1:10 Ethyl acetate:ethanol was placed under a hydrogen atmosphere at 20 PSI and shaken for 4 hours. The resultant mixture was filtered through a celite pad and concentrated under reduced pressure. The crude solid residue was purified by column chromatography, eluting the desired product from silica gel with a gradient of 0-30% ethyl acetate in hexanes: 75 mg of a white solid. MS (ESI+): m/z 385.0 (M+1).
Reaction SMILES: CC1C=CC=C(C)C=1C(C1C=C(OC)C=CC=1OC)N(C1C=CN=C([NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])=[CH:23][CH:22]=2)N=1)C(=O)[O-].[CH3:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH3:50])[C:45]=1[O:51][C:52](=[O:72])[N:53]([C:65]1[CH:70]=[CH:69][N:68]=[C:67](Cl)[N:66]=1)[CH2:54][C:55]1[CH:60]=[C:59]([O:61][CH3:62])[CH:58]=[CH:57][C:56]=1[O:63][CH3:64].CN(C)CCOC1C=CC(N)=CC=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].O>>[CH3:64][O:63][C:56]1[CH:57]=[CH:58][C:59]([O:61][CH3:62])=[CH:60][C:55]=1[CH2:54][N:53]([C:65]1[CH:70]=[CH:69][N:68]=[C:67]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])=[CH:25][CH:26]=2)[N:66]=1)[C:52](=[O:72])[O:51][C:45]1[C:46]([CH3:50])=[CH:47][CH:48]=[CH:49][C:44]=1[CH3:43]
Reactant: COc1ccc(OC)c(CN(C(=O)Oc2c(C)cccc2C)c2ccnc(Cl)n2)c1
Reactant: COc1ccc(OC)c(C(c2c(C)cccc2C)N(C(=O)[O-])c2ccnc(Nc3ccc(OCCN(C)C)cc3)n2)c1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: CN(C)CCOc1ccc(N)cc1
Agent: O=C([O-])[O-]
Solvent: O
Product: COc1ccc(OC)c(CN(C(=O)Oc2c(C)cccc2C)c2ccnc(Nc3ccc(OCCN(C)C)cc3)n2)c1
Temperature: 100 °C

Procedure:
2,6-dimethylphenyl(2,5-bis(methyloxy)phenyl)methyl(2-((4-((2-(dimethylamino)ethyl)oxy)phenyl)amino)-4-pyrimidinyl)carbamate A resealable tube was charged with the (2-chloropyrimidin-4-yl)-(2,5-dimethoxy-benzyl)carbamic acid 2,6-dimethylphenyl ester (0.200 g, 0.467 mmol), 4-(2-dimethylaminoethoxy)phenylamine (0.088 g, 0.490 mmol), tris(dibenzylidene-acetone)-di-palladium (0.017 g, 0.019 mmol), 4,5-bis-diphenylphosphanyl-9,9-dimethyl-9H-xanthene (0.032 g, 0.056 mmol), and sodium carbonate (0.069 g, 0.653 mmol). The system was flushed with argon and toluene (3 mL) was added followed by the addition of water (0.010 mL, 0.467 mmol) (with stirring). The tube was flushed with argon and sealed. The mixture was heated at 100° C. for 16 h and then cooled to room temperature. The reaction mixture was filtered, and the filtrate was concentrated to afford a brown oil. The oil was purified via column chromatography (gradient elution with 0-100% dichloromethane-(90:10:1, dichloromethane/methanol/ammonium hydroxide)) to afford 2,6-dimethylphenyl (2,5-bis(methyloxy)phenyl)methyl(2-((4-((2-(dimethylamino)ethyl)oxy)-phenyl)amino)-4-pyrimidinyl)carbamate as a yellow solid. MS (MH+) 572.3; Calculated 571.67 for C32H37N5O5.