Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH2:20][O:21][CH2:22][CH3:23])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:47][O:48][C:49]1[N:54]=[C:53]2[S:55][C:56]([NH2:58])=[N:57][C:52]2=[CH:51][CH:50]=1.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH2:20][O:21][CH2:22][CH3:23])(=[O:18])=[O:19])=[CH:13][CH:12]=2)[C:8]([NH:58][C:56]2[S:55][C:53]3[C:52]([N:57]=2)=[CH:51][CH:50]=[C:49]([O:48][CH3:47])[N:54]=3)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc2nc(N)sc2n1
Reactant: CCOCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc3ccc(OC)nc3s2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of the title D compound, 3-cyclopentyl-2-(4-ethoxymethylsulfonyl-phenyl)-propionic acid (1 g, 0.0029 mol), HOBt (596 mg, 0.0044 mol), EDCl hydrochloride (846 mg, 0.0044 mol) and 583 mg (0.0032 mol) of the title E compound, 5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine in DCM is treated with DIEA (2 mL, 0.011 mol). The reaction is stirred at 25° C. for 24 h. The reaction mixture is treated with saturated aqueous sodium bicarbonate solution and washed with water. The resulting organic layer is then washed with 1 N aqueous hydrochloric acid solution followed by water and brine. The organic layer is dried over sodium sulfate, filtered and evaporated under vacuum. The crude product is purified by column chromatography over Silica gel (60-120 mesh) using 80/20—hexane/ethyl acetate to give 3-cylcopentyl-2-(4-ethoxymethylsulfonyl-phenyl)-N-(5-methoxythiazolo[5,4-b]pyridin-2yl)-propionamide as a white solid: MS e/z (ES) 502.13 (M−1−, 100%); m.p. 158-160° C.; 1H NMR δ 12.7 (s, 1H), 8.02 (d, J=8.4, 1H), 7.88 (d, J=7.2, 2H), 7.69 (d, J=7.6, 2H), 6.91 (d, J=8.8, 1H), 4.81 (s, 2H), 4.10 (m, 1H), 3.90 (s, 3H), 3.73 (m, 2H), 2.14-2.17 (m, 1H), 1.83-1.85 (m, 1H), 1.60-1.73 (m, 2H), 1.50-1.59 (m, 3H), 1.40-1.52 (m, 2H), 1.10-1.15 (m, 2H), 1.02-1.12 (m, 3H).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[F:18])[C:12](O)=[O:13].COC(Cl)=O>O1CCCC1>[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[F:18])[CH2:12][OH:13]
Reactant: O=C(O)c1ccc(F)c(Br)c1
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OCc1ccc(F)c(Br)c1
Reaction time: 0.67 h
Yield: 49.6 %

Procedure:
2 g of triethylamine, dissolved in 5 ml of tetrahydrofuran, were added dropwise to a solution of 4.2 g of 3-bromo-4-fluoro-benzoic acid and 1.95 g of chloroformic acid methyl ester in 30 ml of tetrahydrofuran at 20° C., while stirring. Stirring was continued for a further 40 minutes at 20°-25° C. and the hydrochloride which had precipitated was then filtered off. 5.5 g of sodium borohydride, dissolved in 20 ml of water, were added dropwise to the filtrate at 10° to 20° C., while stirring. Stirring was then continued for a further 4 hours at 20° C. The reaction batch was subsequently poured into 100 ml of water and extracted by shaking with 80 ml of methylene chloride. The methylene chloride phase was separated off and dried over magnesium sulphate and the solvent was then distilled off in vacuo. 1.95 g (95% of theory) of 3-bromo-4-fluoro-benzyl alcohol were obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4](I)[CH:3]=1.C([O-])(=O)C.[Na+].[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19].C(O)(=O)C>C(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Fe].O.CN1CCCC1=O>[NH2:8][C:6]1[CH:5]=[C:4](/[CH:19]=[CH:18]/[C:17]([O:21][CH3:22])=[O:20])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)cc(I)c1
Reactant: C=CC(=O)OC
Agent: [Fe]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN1CCCC1=O
Solvent: CCO
Solvent: O
Product: COC(=O)/C=C/c1cc(N)cc(F)c1
Temperature: 130 °C
Reaction time: 14 h
Yield: 39.2 %

Procedure:
A mixture of 1-fluoro-3-iodo-5-nitrobenzene (1.145 g, 4.29 mmol), sodium acetate (0.430 g, 5.24 mmol), palladium(II) acetate (1.7 mg, 0.0076 mmol), methyl acrylate (0.425 mL, 4.71 mmol), and 1-methyl-2-pyrrolidinone (11 mL) under argon was degassed with three freeze/pump/thaw cycles. The reaction mixture was heated to 130° C. for 35 min and then at 100° C. for 14 h. The reaction mixture was diluted with water and saturated sodium bicarbonate solution and extracted three times with diethyl ether. The combined organic extracts were washed with saturated sodium bicarbonate solution, hydrochloric acid (1 N), and brine, dried (MgSO4), and concentrated under reduced pressure. The residue was suspended in a mixture of ethanol (12 mL), water (2.5 mL), and acetic acid (1.25 mmol) and heated to reflux. Iron powder (0.519 g, 9.28 mmol) was added portionwise over 30 min, and reflux was continued for an additional 30 min. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and sodium bicarbonate solution and filtered through a glass fibre filter to remove a fine grey precipitate. The aqueous phase was extracted with ethyl acetate (3×) and the organic phase was dried (MgSO4) and concentrated under reduced pressure to give 19A (0.328 g, 74%) as a pale yellow solid. LC-MS m/z: 196.2 (M+H)+.
Reaction SMILES: N1CCCCC1.[Cl:7][C:8]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:9]=1[CH:10]=O.C(O)(=O)[CH2:20][C:21]([OH:23])=[O:22].C(=O)=O.Cl>N1C=CC=CC=1>[Cl:7][C:8]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:9]=1[CH:10]=[CH:20][C:21]([OH:23])=[O:22]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: O=C(O)CC(=O)O
Agent: Cl
Agent: O=C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cc([N+](=O)[O-])ccc1Cl
Temperature: 0 °C

Procedure:
8.5 g of piperidine were added to 185.5 g (1 mole) of 2-chloro-5-nitrobenzaldehyde and 125 g (1.2 moles) of malonic acid in 400 ml of pyridine, and the mixture was stirred at 110° C. until the evolution of CO2 was complete (about 3 hours). The reaction mixture was then poured on to a mixture of 1 l of ice and 350 ml of concentrated HCl, a yellow solid being precipitated. The product was filtered off under suction, washed with water and dried to give 220 g (97% of theory) of the above compound of melting point 193°-196° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH2:8].[CH3:9][N:10]([CH3:31])[CH2:11][CH:12]([N:14]1[C:27]2[CH:26]=[C:25]([C:28](=S)N)[CH:24]=[CH:23][C:22]=2[S:21][C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13]>C(OCC)(=O)C>[CH3:31][N:10]([CH3:9])[CH2:11][CH:12]([N:14]1[C:27]2[CH:26]=[C:25]([C:28]3[NH:8][CH:3]4[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]4[N:1]=3)[CH:24]=[CH:23][C:22]=2[S:21][C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13]
Reactant: NC1CCCCC1N
Reactant: CC(CN(C)C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Solvent: CCOC(C)=O
Product: CC(CN(C)C)N1c2ccccc2Sc2ccc(C3=NC4CCCCC4N3)cc21
Temperature: 160 °C
Yield: 36.2 %

Procedure:
1,2-Diaminocyclohexane (9.3 g) is added to an ethanolic solution (35 cc) of 10-[(2RS)-1-dimethylamino-2-propyl]-2-phenothiazinecarbothioamide (2.8 g). The mixture is heated in an autoclave to 160° C. for 4.5 hours. The reaction mixture is diluted with ethyl acetate (100 cc) and washed with distilled water (3×100 cc). The organic phase is separated after settling has taken place, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is purified by chromatography on a column (height: 22 cm; diameter: 4 cm) of silica gel (0.04-0.06 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with 1,2-dichloroethane (1 liter) and mixtures of 1,2-dichloroethane and methanol in proportions (by volume) of 90:10 (3 liters), 80:20 (2 liters), 70:30 (2 liters) and 50:50 (1 liter) and with pure methanol (1 liter) and collecting 125-cc fractions. Fractions 63 to 80 containing the pure product are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give 10-[(2RS)-1-dimethylamino-2-propyl]-2-(3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl)phenothiazine (1.2 g) in the form of a yellow product of meringue-like consistency.
Reaction SMILES: [OH-].[CH2:2]([N+:6]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][CH3:5].[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[NH:27][C:28](=[O:34])/[CH:29]=[CH:30]\[C:31]([OH:33])=[O:32].C(O)(=O)C>CO>[CH2:15]([N+:6]([CH2:2][CH2:3][CH2:4][CH3:5])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17][CH3:18].[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[NH:27][C:28](=[O:34])/[CH:29]=[CH:30]\[C:31]([O-:33])=[O:32]
Reactant: Cc1cccc(C)c1NC(=O)/C=C\C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cccc(C)c1NC(=O)/C=C\C(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 111.5 %

Procedure:
39 g (0.06 mole) of tetrabutylammonium hydroxide solution (40% in water) is added to the suspension of 13.15 g of N-(2,6-dimethylphenyl)-maleamic acid in 100 ml of methanol, and the reaction mixture is stirred for one hour at room temperature. The pH-value is adjusted to about 7.0 with acetic acid, and the solvent is removed in vacuo in a rotary evaporator to leave 30.8 g of N-(2,6-dimethylphenyl)-maleamic acid tetrabutylammonium salt in the form of yellow oil, which crystallises on prolonged standing.
Reaction SMILES: [CH3:1][CH:2]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][O:13][C:12](=[O:18])[C:11]1([CH2:20][CH3:21])[CH3:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:22](OOC(C)(C)C)(C)(C)C>C(C1C=CC=CC=1)C>[CH3:1][CH:2]([O:9][N:10]1[C:15]([CH3:16])([CH3:17])[CH2:14][O:13][C:12](=[O:18])[C:11]1([CH2:19][CH3:22])[CH2:20][CH3:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: CCC1(C)C(=O)OCC(C)(C)N1OC(C)c1ccccc1
Solvent: CCc1ccccc1
Product: CCC1(CC)C(=O)OCC(C)(C)N1OC(C)c1ccccc1
Yield: 52 %

Procedure:
In analogy to Example B3, compound (206), 4.75 g (0.026 mol) of 3,3-diethyl-5,5-dimethylmorpholin-2-on-4-oxyl are reacted with t-butylperoxide and ethylbenzene as solvent, resulting in 4.1 g (52%) of compound (210) in the form of a colourless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=2)[NH:9][CH:8]=1)=O.C(#N)C.C([BH3-])#N.[Na+].Cl>O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=2)[NH:9][CH:8]=1
Reactant: N#Cc1ccc2[nH]cc(C(=O)CCCO)c2c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc2[nH]cc(CCCCO)c2c1
Temperature: 2.5 °C
Reaction time: 0.08 h
Yield: 89.5 %

Procedure:
3-(4-Hydroxybutyryl)-1H-indole-5-carbonitrile (50 g) was added to acetonitrile (750 ml) at 25-30° C., followed by the addition of sodium cyanoborohydride (75 g) at the same temperature. The resulting mixture was cooled to 0-5° C., followed by drop-wise addition of a mixture of concentrated HCl (112.5 ml) and water (112.5 ml) for a period of 15 minutes at the same temperature. After completion of the reaction, water (750 ml) was added to the reaction mass at 0-5° C., followed by stirring for 5 minutes at the same temperature. The layers were separated and the aqueous layer was extracted two times with toluene (2×1000 ml). The resulting organic layers were combined, washed two times with water (2×1000 ml), and then distilled off the solvent under vacuum to produce 42 g of the titled compound as a residue. Dichloromethane (420 ml) was added to the residue at 25-30° C. to form a clear solution, followed by filtration to remove undissolved particles. The resulting filtrate was cooled to −5° C. to 0° C. and then stirred for 1-2 hours at the same temperature. The separated solid was filtered, washed with chilled dichloromethane (42 ml) and then dried at 50-55° C. to produce 31 g of 3-(4-hydroxybutyl)-1H-indole-5-carbonitrile (Purity by HPLC: 99%). The mother liquors were taken and distilled off the solvent under vacuum to give 11 g of the titled compound as a residue (Total yield: 86%).
Reaction SMILES: [F:1][C:2]([F:28])([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].C1(P([N:43]=[N+:44]=[N-:45])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CC(O)(C)C>[F:28][C:2]([F:1])([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([N:43]=[N+:44]=[N-:45])=[O:25])=[CH:21][CH:20]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:3]([F:5])([F:6])[F:4]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1

Procedure:
A solution of 4-[1-(4-pentafluoroethyloxy-phenyl)-1H-[1,2,4]triazol-3-yl]-benzoic acid (1.67 g, 4.2 mmol), diphenylphosphoryl azide (1.26 g, 4.58 mmol) and triethylamine (0.5 g, 5 mmol) in 10 mL of dry t-BuOH was heated to 75° C. for 90 min, resulting in dissolution of the starting acid and subsequent precipitation of the azide. The cooled solution was then poured onto 10 g of ice, and the resulting mixture was filtered and dried to furnish 0.80 g of the azide as a white solid. 1H NMR (300 MHz, CDCl3) δ 10.1 (s, 1H), 8.65 (s, 1H), 8.40 (d, J=8.4 Hz, 2H), 8.0 (d, J=8.4 Hz, 2H), 7.85 (d, J=9 Hz, 2H), 7.45 (d, J=9 Hz, 2H); ESIMS 399.2 (M+H); mp 175° C. dec.
Reaction SMILES: C(Cl)CCl.ClC(Cl)C(O)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[CH:21][N:20]([C:23]3[N:52]=[CH:51][CH:50]=[CH:49][C:24]=3[C:25]([NH:27][CH:28]([CH:36]([OH:48])[C:37](=[O:47])[NH:38][CH2:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:26])[N:19]=2)=[CH:14][CH:13]=1.C([O-])(O)=O.[Na+]>CS(C)=O.[Cl-].[Na+].O>[O:48]=[C:36]([C:37](=[O:47])[NH:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH:28]([NH:27][C:25]([C:24]1[C:23]([N:20]2[CH:21]=[CH:22][C:18]([C:15]3[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=3)=[N:19]2)=[N:52][CH:51]=[CH:50][CH:49]=1)=[O:26])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)NCCc1ccccc1)c1cccnc1-n1ccc(-c2ccc(F)cc2)n1
Agent: O=C(O)C(Cl)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCCl
Product: O=C(NCCc1ccccc1)C(=O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 48.3 %

Procedure:
EDC (520 mg, 2.71 mmol) and 2,2-dichloroacetic acid (0.14 ml, 1.69 mmol) were added to a solution of 2-(3-(4-fluorophenyl)-1H-pyrazol-1-yl)-N-(3-hydroxy-4-oxo-4-(phenethylamino)-1-phenylbutan-2-yl)nicotinamide (191 mg, 0.339 mmol) in dimethyl sulfoxide (DMSO) (9 ml), and the reaction mixture was stirred for 45 minutes at room temperature. For work up the reaction mixture was mixed with 100 ml of brine and sat. solution of NaHCO3 (1:1(v/v)) for 10 minutes. The resulting solid was filtered off with suction, washed with water and dried to give 161 mg of the crude product, which was re-crystallized from ethyl acetate to give 92 mg of a white amorphous solid; ESI-MS [M+H]+: 562.3.
Reaction SMILES: NC1C(OC2C=CC=CC=2)=NC=C(OC)N=1.N([O-])=O.[Na+].O[C:22]1[C:27]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[N:26][CH:25]=[C:24]([O:34][CH3:35])[N:23]=1.P(Cl)(Cl)([Cl:38])=O>>[Cl:38][C:22]1[C:27]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[N:26][CH:25]=[C:24]([O:34][CH3:35])[N:23]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cnc(N2CCOCC2)c(O)n1
Agent: COc1cnc(Oc2ccccc2)c(N)n1
Agent: O=N[O-]
Agent: [Na+]
Product: COc1cnc(N2CCOCC2)c(Cl)n1

Procedure:
The 2-amino substituent of Step A product when treated with sodium nitrite as described in Step E of Preparation 81 is converted to the 2-hydroxy group. Treatment of the 2-hydroxy-3-morpholino-6-methoxypyrazine with phosphorus oxychloride by Preparation 13, Step B method, gives 2-chloro-3-morpholino-6-methoxypyrazine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[NH:8][C:7]1([CH3:15])[CH3:14].C(O[Cl:21])(C)(C)C>CO>[Cl:21][N:8]1[C:9]([CH3:13])([CH3:12])[C:10](=[O:11])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][OH:1])[C:7]1([CH3:15])[CH3:14]
Reactant: CC(C)(C)OCl
Reactant: CC1(C)NC(C)(C)N(CCCCO)C1=O
Solvent: CO
Product: CC1(C)C(=O)N(CCCCO)C(C)(C)N1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.5 %

Procedure:
To a 0° C. solution of 3-(4-hydroxybutyl)-2,2,5,5-tetramethylimidazolidin-4-one, (622 mg, 2.9 mmol) in methanol (80 ml) was added tert-butylhypochlorite (473 mg, 4.4 mmol). The mixture was stirred for 1 hour at 0° C. The reaction mixture was concentrated in vacuo, and crude material is purified by silica gel flash chromatography (0 to 15% methanol in dichloromethane) to give 213 mg (30%) of the title compound. 1H NMR (400 MHz, D2O) δ 3.74-3.66 (m, 2H), 3.34-3.30 (m, 2H), 2.08 (s, 1H), 1.78-1.71 (m, 2H), 1.65-1.57 (m, 2H), 1.47 (s, 6H), 1.36 (s, 6H). 13C NMR (100 MHz, D2O) δ 173.0, 82.3, 65.5, 62.5, 40.5, 29.8, 26.1, 25.5, 23.8. LRMS (ESI/APCI) m/z 249 [M+H]+.
Reaction SMILES: C(OC1N=C2C(N=C(OC)N2CCCC2CCCCN2)=C(N)N=1)CCC.[NH2:27][C:28]1[N:36]=[C:35]([O:37][C@@H:38]([CH3:42])[CH2:39][CH2:40][CH3:41])[N:34]=[C:33]2[C:29]=1[N:30]=[C:31]([O:60][CH3:61])[N:32]2[CH2:43][CH:44]1[CH2:49][CH2:48][N:47](C(OCC2C=CC=CC=2)=O)[CH2:46][CH2:45]1>>[CH3:42][C@H:38]([O:37][C:35]1[N:34]=[C:33]2[C:29]([N:30]=[C:31]([O:60][CH3:61])[N:32]2[CH2:43][CH:44]2[CH2:45][CH2:46][NH:47][CH2:48][CH2:49]2)=[C:28]([NH2:27])[N:36]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CC3CCN(C(=O)OCc4ccccc4)CC3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CC3CCNCC3)c2n1

Procedure:
Prepared similarly to Intermediate 32 from phenylmethyl 4-{[6-amino-2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-9-yl]methyl}-1-piperidinecarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:12]([CH3:13])=[CH:11][S:10][C:9]=2[CH:14]=1)=[O:4].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:12]([CH2:13][Br:15])=[CH:11][S:10][C:9]=2[CH:14]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(C)csc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(CBr)csc2c1
Yield: 56.2 %

Procedure:
A mixture of 3-methylbenzo[b]thiophene-6-carboxylic acid methyl ester (1.03 g), N-bromosuccinimide (0.89 g), azobisisobutyronitrile (0.2 g) and carbon tetrachloride (25 ml) was heated under reflux for 2 hours and then cooled. The mixture was diluted with a few ml. of chloroform, washed with water, dried (Na2SO4) and evaporated to give a solid which was crystallized from ethyl acetate/petrol (b.p. 60°-80° C.) to give 3-bromomethylbenzo[b]thiophene-6-carboxylic acid methyl ester (0.80 g), m.p. 108°-110° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[CH3:23][NH:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][N:33]=1)[C:28](O)=[O:29]>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:28]([C:27]3[CH:31]=[CH:32][N:33]=[C:25]([NH:24][CH3:23])[CH:26]=3)=[O:29])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: CNc1cc(C(=O)O)ccn1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Agent: Cl
Product: CNc1cc(C(=O)N2CCCC[C@@H]2COc2cccc3c2C(N)=NS(=O)(=O)N3)ccn1

Procedure:
Prepared as in Example 15 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and 2-(methylamino)isonicotinic acid. 1H NMR (400 MHz, DMSO-d6) δ 1.41 (m, 1H), 1.52-1.74 (m, 4H), 1.83 (m, 1H), 2.74 (d, 3H, J=4.6 Hz), 3.19 (m, 1H), 3.40 (m, 1H), 4.19 (dd, 1H, J=9.9, 3.6 Hz), 4.65 (t, 1H, J=10.1 Hz), 5.20 (m, 1H), 6.30 (s, 1H), 6.61 (m, 2H), 6.88 (d, 1H, J=8.5 Hz), 7.46 (t, 1H, J=8.6 Hz), 7.83 (br s, 1H), 8.01 (d, 1H, J=5.4 Hz), 8.30 (br s, 1H), 10.93 (s, 1H). MS 445 (MH+).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][NH:3][CH2:2]1.CCN(CC)CC.[O:19](C(C(F)(F)F)=O)[C:20]([C:22]([F:25])([F:24])[F:23])=O>C(Cl)Cl>[F:23][C:22]([F:25])([F:24])[C:20]([N:3]1[CH2:2][CH2:1][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4]1)=[O:19]
Reactant: c1ccc2c(c1)CCNCC2
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N1CCc2ccccc2CC1)C(F)(F)F
Reaction time: 1 h
Yield: 101.1 %

Procedure:
To a stirred solution of 2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.25 g, 1.7 mmol) in anhydrous CH2Cl2 (5 ml), Et3N (0.28 ml, 2 mmol) was added at 0° C. and under N2, followed by (CF3CO)2O (0.29 ml, 2 mmol) and the resulting mixture was stirred for 1 h, than washed with aqueous NaHCO3 and H2O. The organic layer was dried over MgSO4, filtered and the filtrate was evaporated to dryness to give the title product (0.418 g, 100%), as pale oil. 1H-NMR (CDCl3) 3.6-3.97 (m, 8H); 7.11-7.19 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[O:5][CH2:6][C:7]([OH:9])=O.[CH2:14]1COC[CH2:15]1.C([Mg]Br)=C.Cl>COCCOC>[CH:14]([C:7]([CH2:6][O:5][C:4]1[CH:10]=[CH:11][C:12]([F:13])=[C:2]([F:1])[CH:3]=1)=[O:9])=[CH2:15]
Reactant: C1CCOC1
Reactant: O=C(O)COc1ccc(F)c(F)c1
Agent: C=C[Mg]Br
Agent: Cl
Solvent: COCCOC
Product: C=CC(=O)COc1ccc(F)c(F)c1
Reaction time: 18 h

Procedure:
To a suspension of 3,4-difluorophenoxy acetic acid (5.00 g, 25.7 mmol) lithium salt in DME (20 mL) was added to a 1 M THF solution of vinyl magnesium bromide (38 mmol). After a period of 18 h, the resulting clear solution was poured over 1 N HCl (67 mL). The aqueous phase was then extracted with Et2O. The ethereal phase was washed with H2O, 1 M K2CO3 then H2O. After drying over MgSO4 and evaporation an orange oil was obtained and used as such for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:11](OCC)(=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].[H-].[Na+].Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH2:9][C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cccc(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=O)CC(=O)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To an ice-cold solution of 1-(3-chlorophenyl)ethanone (16.79 mL, 129 mmol) and diethyl oxalate (18.05 mL, 136 mmol) in DMF (78.0 mL) was added, portionwise over 30 min., NaH (6.09 g, 155 mmol, 60% dispersion in mineral oil) and the resultant mixture was stirred at that temperature for 20 min. and then at room temperature for 16 h. The reaction mixture was diluted with water and acidified to pH=4-5 with 1N aq. HCl. The mixture was further diluted with copious amounts of water. The aq. layer was extracted with EtOAc (4×100 mL) and the combined organic layer was washed with water, brine, dried over anhydrous MgSO4, filtered and the filtrate was concentrated under reduced pressure to provide a crude residue. It was purified by silica gel chromatography (220 g REDISEP® column, eluting with a 0 to 15% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate A1C (27.1 g, 84%) as a solid. MS(ES): m/z=277.10 [M+Na]+; 1H NMR (400 MHz, chloroform-d) δ ppm 7.99 (t, J=1.8 Hz, 1H), 7.95-7.86 (m, 1H), 7.60 (ddd, J=8.0, 2.1, 1.0 Hz, 1H), 7.48 (t, J=7.9 Hz, 1H), 7.06 (s, 1H), 4.43 (q, J=7.3 Hz, 2H), 1.44 (t, J=7.2 Hz, 3H).