Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]([CH3:18])[CH3:17])[C:11]=1[N:19]=[C:20]([C:22]1[CH:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])[CH:25]=[CH:26][CH:27]=1)[CH3:21])([CH3:9])[CH3:8].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]([CH3:18])[CH3:17])[C:11]=1[NH:19][CH:20]([C:22]1[CH:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])[CH:25]=[CH:26][CH:27]=1)[CH3:21])([CH3:8])[CH3:9]
Reactant: COc1ccccc1-c1cccc(C(C)=Nc2c(C(C)C)cccc2C(C)C)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccccc1-c1cccc(C(C)Nc2c(C(C)C)cccc2C(C)C)c1

Procedure:
To a suspension of 0.70 g (18.4 mmol) of LiAlH4 in 60 mL of THF, 2.25 g (5.84 mmol) of 39 was added. This reaction mixture was refluxed for 2 hr, and then saturated aqueous Na2SO4 was added. The organic layer was separated, and the aqueous layer was extracted with 2×50 mL of diethyl ether. The combined organic extract was evaporated to dryness, and the product was isolated by flash chromatography on silica gel 60 (40-63 um, eluent: hexanes-diethyl ether from 100:1 to 20:1, vol.) to yield 1.45 g (64%) of Fl.
Reaction SMILES: FC1C=CC(CN2C3C=CC=CC=3N=C2)=CC=1.CCCCCC.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][CH:37]([C:40](OC)=[O:41])[CH2:36][CH2:35]2)=[CH:28][CH:27]=1>C1COCC1>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][CH:37]([CH:40]=[O:41])[CH2:36][CH2:35]2)=[CH:28][CH:27]=1
Reactant: COC(=O)C1CCN(CCc2ccc(OC)cc2)CC1
Agent: Fc1ccc(Cn2cnc3ccccc32)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(CCN2CCC(C=O)CC2)cc1
Reaction time: 0.29 h

Procedure:
To a stirred, -78° C., solution of 1-[(4-fluorophenyl)methyl]-1H-benzimidazol (1.13 g, 5.00×10-3 mole) and dry THF (12 ml) under argon was added a 2.5 molar hexane solution of n-butyl ithium (2.1 ml, 5.25×10-3 mole). After 15-20 minutes at -78° C., a solution of 1-[2-(4-methoxyphenyl)ethyl]-4-piperidinecarboxylic acid, methyl ester (1.39 g, 5.01×10-3 mole) and dry THF (6 ml) was added dropwise via syringe. After 5-10 minutes, the cooling bath was removed and the reaction was allowed to warm. After ca. 30 minutes, the reaction was quenched by the addition of saturated aqueous NH4Cl. The reaction was transferred to a separatory funnel where the aqueous mixture was extracted two times with ethyl acetate. The ethyl acetate extracts were combined, washed with saturated aqueous NaCl, and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure affording a viscous oil. This was purified by a combination of flash chromatography (ethyl acetate) and crystallization (cyclohexane) affording 1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl][1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]methanone as off white matted needles: 0.90 g (38%), m.p. 109°-111° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:17]=[N:16]2)[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1)#[N:2].Br[C:30]1[C:31]([CH3:36])=[N:32][NH:33][C:34]=1[CH3:35].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18]([C:30]3[C:31]([CH3:36])=[N:32][NH:33][C:34]=3[CH3:35])[CH:17]=[N:16]2)[CH2:5][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Reactant: Cc1n[nH]c(C)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1n[nH]c(C)c1-c1cnn(C2(CC#N)CN(C(=O)OC(C)(C)C)C2)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 25.7 %

Procedure:
A mixture of tert-butyl 3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (381 mg, 0.981 mmol, from Example 1, step 2), 4-bromo-3,5-dimethyl-1H-pyrazole (206 mg, 1.18 mmol), tetrakis(triphenylphosphine)palladium(0) (110 mg, 0.098 mmol) and sodium carbonate (310 mg, 2.9 mmol) in 1,4-dioxane (10 mL) and water (5 mL) was purged with N2 and stirred at 110° C. for 2 h. The reaction mixture was filtered, diluted with EtOAc, then washed with water. The organic layer was concentrated and purified on silica gel (eluting with 0-100% EtOAc/hexanes followed by 0-10% MeOH/dichloromethane) to give tert-butyl 3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidine-1-carboxylate (90 mg, 26%). LCMS calculated for C18H25N6O2 (M+H)+: m/z=357.2. Found: 357.2. This intermediate was treated with 4.0 M hydrogen chloride in dioxane (1.2 mL, 4.9 mmol) in methylene chloride (1 mL) at rt for 2 h. The mixture was stripped to dryness to give the desired product. LCMS calculated for C13H17N6 (M+H)+: m/z=257.1. Found: 257.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]2[C:13](Br)=[C:12]([N+:15]([O-:17])=[O:16])[CH:11]=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:18]([NH2:21])([CH3:20])[CH3:19]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([N:9]2[C:13]([NH:21][CH:18]([CH3:20])[CH3:19])=[C:12]([N+:15]([O-:17])=[O:16])[CH:11]=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=[N+]([O-])c1cnn(-c2ncc(Cl)cc2Cl)c1Br
Reactant: CC(C)N
Solvent: ClCCl
Product: CC(C)Nc1c([N+](=O)[O-])cnn1-c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.3 %

Procedure:
A mixture of 5.1 g (0.015 mol) of 1-(3,5-dichloropyrid-2-yl)-4-nitro-5-bromopyrazole and 13.4 g (0.225 mol) of isopropylamine in 100 ml of methylene chloride is stirred at room temperature for 20 hours. The reaction mixture is evaporated in vacuo, the residue is taken up in 50 ml of methylene chloride and washed twice with 50 ml of water; the organic phase is dried over sodium sulphate and the solvent is distilled off in vacuo. The residue is crystallized by rubbing with petroleum ether, filtered off by suction and dried. 4.0 g (84.4% of theory) of 1-(3,5-dichloropyrid-2-yl)-4-nitro-5-isopropylaminopyrazole with a melting point of 123° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]2[N:7]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:6]=[CH:5][C:4]=2[C:3]=1[CH:22]=[O:23].[CH:24]([Mg]Br)=[CH2:25].[NH4+].[Cl-].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1.O>[CH3:1][C:2]1[C:3]([C:22](=[O:23])[CH:24]=[CH2:25])=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: C=C[Mg]Br
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)c(C)cc(C)c32)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC(=O)c1c(C)cc(C)c2c1ccn2S(=O)(=O)c1ccc(C)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 5,7-dimethyl-1-tosyl-1H-indole-4-carbaldehyde (Example 46-D) (500 mg, 1.53 mmol) in THF (15 mL) at −78° C., vinylmagnesium bromide (2.29 mL, 2.29 mmol) was added and the reaction was stirred for 15 minutes. At this point a saturated water solution of NH4Cl was added. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organics were dried over MgSO4 and evaporated. The resulting residue was dissolved in DCM (4 mL), and Dess-Martin Periodinane (1.19 g, 2.81 mmol) was added. After 15 minutes the reaction was complete. The reaction was quenched with a sat. aq. solution of NaHCO3 and sodium thiosulfate. The layers were separated and the aqueous layer was extracted with DCM. It was purified using FCC eluting with heptane/EtOAc 1:1 to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J=3.79 Hz, 1H), 7.50-7.66 (m, J=8.34 Hz, 2H), 7.30-7.45 (m, J=8.34 Hz, 2H), 7.01 (s, 1H), 6.71 (dd, J=10.48, 17.56 Hz, 1H), 6.59 (d, J=4.04 Hz, 1H), 6.14 (d, J=10.86 Hz, 1H), 5.88 (d, J=17.43 Hz, 1H), 2.35 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[O:7][CH:8]=1)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[O:7]1[CH:8]=[C:4]([CH2:3][CH2:1][NH2:2])[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]1=2
Reactant: N#CCc1coc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: NCCc1coc2ccccc12
Yield: 79.4 %

Procedure:
A solution of 3.97 g (0.025 mole) of 3-cyanomethylbenzo[b]furan in 200 mL of diethyl ether was slowly added to a refluxing suspension of 3.84 g (0.1 mole) of lithium aluminum hydride in 400 mL of ether. The reaction was heated 3 hrs., cooled and water was slowly added. The suspension was filtered through a pad of filter aid and the filtrate was evaporated to give 3.2 g of oily product. The hydrochloride salt has m.p. 183°-185° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.[CH2:24]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O)[CH2:25][CH3:26]>>[CH2:20]([C:14]1[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]2[C:5]3[CH:4]=[CH:3][C:2]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[O:27][CH2:24][CH2:25][CH3:26])=[CH:11][C:10]=3[N:9]=[C:8]([NH2:12])[C:7]=2[N:13]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)C
Reactant: CCCOc1ccccc1B(O)O
Product: CCCCc1nc2c(N)nc3cc(-c4ccccc4OCCC)ccc3c2n1CC(C)C

Procedure:
7-Bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and 2-propoxybenzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. The product was recrystallized from isopropanol, collected by filtration, dissolved in CH2Cl2, and then precipitated with hexanes to afford 2-butyl-1-isobutyl-7-(2-propoxyphenyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, m.p. 174.5-176.0° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[NH4+:12].[OH-]>[Cu].C(O)(C)C>[NH2:12][C:2]1[CH:11]=[N:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: [NH4+]
Reactant: Clc1cnc2c(n1)CCCC2
Agent: [Cu]
Agent: [OH-]
Solvent: CC(C)O
Product: Nc1cnc2c(n1)CCCC2
Temperature: 133 °C

Procedure:
A seated tube containing 2-chloro-5,6,7,8-tetrahydroquinoxaline (1.51 g, 0.009 mol), concentrated NH4OH (10 mL), isopropyl alcohol (30 mL), and copper powder (300 mg) was heated in an oil bath at 133° C. for 20 hours. The cooled mixture was filtered through celite and washed through the filter agent with H2O and hexanes. The layers were separated and the aqueous portion was washed (2×) with hexanes in order to remove unreacted starting material and then extracted with EtOAc (4×). The combined EtOAc extracts were dried over sodium sulfate and concentrated under reduced pressure to yield 2-amino-5,6,7,8-tetrahydroquinoxaline as a yellow-green solid.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][CH:10]([C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[OH:9][CH:10]([C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH:19][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: BrCc1ccccc1
Reactant: CCCCCC(O)c1cccc(N)c1
Product: CCCCCC(O)c1cccc(NCc2ccccc2)c1

Procedure:
For compounds in which X is --NR2 --(CHR1)n --, the corresponding amino starting compounds are employed to form the desired amino compound. Thus, aniline is condensed with 3-(1-hydroxyhexyl)benzylbromide to form 2-[3-(1-hydroxyhexyl)benzylamino]benzene. Alternatively, benzyl bromide is condensed with 3-(1-hydroxyhexyl)aniline to form 2-[3-(1-hydroxyhexyl)anilinomethyl]benzene.
Reaction SMILES: Br.[CH3:2][C@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.CS(O[CH2:13][CH2:14][C:15]1[O:16][C:17]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)=[CH:20][C:18]=2[CH:19]=1)(=O)=O>>[CH3:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:13][CH2:14][C:15]1[O:16][C:17]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)=[CH:20][C:18]=2[CH:19]=1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Reactant: C[C@H]1CCCN1
Agent: Br
Product: C[C@H]1CCCN1CCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1

Procedure:
(2S)-2-Methylpyrrolidine hydrobromide and the product from Example 1C can be processed as described in Example 1D to provide the title compound.
Reaction SMILES: Br[CH:2](Cl)[C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].C([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH:32](C(N)=O)[CH2:31]1)=O)(C)(C)C>CN(C)C=O>[CH3:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:33]1[CH2:34][CH2:35][N:30]([CH:28]=[O:27])[CH2:31][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCNC(C(N)=O)C1
Reactant: Cc1cccc(C)c1NC(=O)C(Cl)Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1NC(=O)CN1CCN(C=O)CC1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
A mixture of 2-bromo,chloro-N-(2,6-dimethylphenyl)acetamide (V: 24.2 g, 0.10 mol), anhydrous sodium carbonate (15.9 g, 0.15 mol), sodium iodide (0.10 g) and 1-piperazine carboxaldehyde (IV: 10.3 mL, 0.10 mol) in anhydrous dimethylformamide (200 mL) was heated to 85° C. for 6 h before it was cooled, suction-filtered and concentrated down in vacuo. The residue was then dissolved in a minimal amount of hot 5% methanol in ethyl acetate. After 2 h at ambient temperature, the mixture was suction-filtered and the filtrate was concentrated down once again to yield a grey-colored solid which was recrystallized from ethyl acetate. There the Formula III compound was isolated 17.95 g (65%) as a white solid, m.p. 139°-140° C.; 1H NMR (300 MHz, CDCl3) δ 8.50 (br s, 1H), 7.99 (s, 1H), 7.25-7.03 (m, 3H), 3.59-5.56 (m, 2H), 3.42-3.39 (m, 2H), 3.17 (s, 2H), 2.66-2.59 (m, 4H), 2.19 (s, 6H); 13C NMR (75 MHz, CDCl3) ppm 167.96, 160.96, 135.18, 133.67, 128.53, 127.55, 61.89, 54.28, 53.21, 45.69, 40.07, 18.83; IR (KBr) 3432, 3274, 2958, 1672, 1506, 1446, 1436, 1148, 1020, 1008, 788 cm-1 ; MS m/z calc'd for C15H22N3O2 276.1712, found 276.1709.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH3:7].[Mg].II.[CH3:11][N:12]([CH3:25])[C:13]1(C#N)[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][CH2:14]1.[NH4+].[Cl-]>O.C1COCC1.C(OCC)C>[CH3:7][O:6][CH2:5][CH2:4][CH2:3][CH2:2][C:13]1([N:12]([CH3:25])[CH3:11])[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][CH2:14]1
Reactant: COCCCCCl
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCCCCC1(N(C)C)CCC2(CC1)OCCO2
Reaction time: 1 h

Procedure:
A solution of 1-chloro-4-methoxy-butane (8.19 g, 66.8 mmol) in abs. ether (12 ml) was added, under an argon atmosphere and with intermittent heating, to magnesium (1.62 g, 66.8 mmol) and I2 in abs. diethyl ether (25 ml). The mixture was stirred for 1 h under reflux until the magnesium had largely dissolved. While cooling with ice, a solution of 8-dimethylamino-1,4-dioxa-spiro[4.5]decane-8-carbonitrile B-1 (10.5 g, 50.1 mmol) in abs. THF (40 ml) was added dropwise. A viscous precipitate formed, and further abs. THF (20 ml) was added for the purpose of better mixing. The mixture was stirred for 24 h at room temperature. NH4Cl solution (20%, 80 ml) and water (100 ml) were added to the mixture, while cooling with ice, the organic phase was separated and the aqueous phase was extracted with ether (3×100 ml). The combined organic phases were washed with saturated NaCl solution (80 ml) and water (80 ml), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography with chloroform/methanol (50:120:19:1).
Reaction SMILES: C([NH:5][C:6]([NH:8][C@@H:9]([CH2:18]O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[S:7])(C)(C)C.[ClH:20]>>[ClH:20].[OH:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C@@H:9]2[CH2:18][S:7][C:6]([NH2:5])=[N:8]2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)NC(=S)N[C@@H](CO)Cc1ccc(O)cc1
Agent: Cl
Product: NC1=N[C@H](Cc2ccc(O)cc2)CS1

Procedure:
A solution of 0.2 g of N-(tert-butyl)-N′-[(1R)-1-hydroxymethyl-2-(4-hydroxyphenyl)ethyl]-thiourea in 2.6 cm3 of 6N hydrochloric acid is heated at a temperature in the region of 110° C. for 18 hours. The reaction medium is concentrated under reduced pressure (1 kPa) at a temperature in the region of 55° C. and is then taken up successively in 10 cm3 of isopropyl ether, 10 cm3 of diethyl ether, 10 cm3 of pentane, 10 cm3 of petroleum ether and 10 cm3 of isopropyl ether, concentrating under the same conditions as above between each wash. The solid obtained is dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 40° C. to give 0.098 g of (+)-(4R)-4-(4-hydroxybenzyl)-4,5-dihydro-2-thiazolyl-amine hydrochloride in the form of an orange-colored solid [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 2.78 (dd, J=13.5 and 7.5 Hz: 1H); 2.88 (dd, J=13.5 and 5.5 Hz: 1H); 3.26 (dd, J=11.5 and 6 Hz: 1H); 3.55 (dd, J=11.5 and 7.5 Hz: 1H); 4.45 (mt: 1H); 6.74 (d, J=8.5 Hz: 2H); 7.07 (d, J=8.5 Hz: 2H); 9.09 (unresolved complex: 1H); 9.41 (s: 1H); 9.56 (unresolved complex: 1H); 9.97 (broad s: 1H); (αD20=+9.5+/−0.5 at a concentration of 0.5% in methanol)].
Reaction SMILES: CI.[C:3]([O-])([O-])=O.[K+].[K+].[C:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])(=[O:12])[CH2:10][CH3:11]>CC(C)=O>[CH3:3][CH:13]([C:9](=[O:12])[CH2:10][CH3:11])[C:14]([O:16][CH3:17])=[O:15]
Reactant: CCC(=O)CC(=O)OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCC(=O)C(C)C(=O)OC
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Methyl iodide (57 ml) and K2CO3 (127 g) were added to a solution of methyl propionylacetate (100 g) in acetone (800 ml) while cooling on ice. The reaction solution was stirred for 96 hours at room temperature and celite filtered, and then the mother liquor was slowly concentrated under reduced pressure and distilled under reduced pressure to obtain methyl 2-methyl-3-oxopentanoate.
Reaction SMILES: Cl.[N:2]1([CH:7]([C:11]2[S:15][C:14]([C:16]([OH:18])=[O:17])=[CH:13][CH:12]=2)[CH2:8][CH2:9][CH3:10])[CH:6]=[CH:5][N:4]=[CH:3]1.Cl>C(O)CCC>[CH2:11]([O:17][C:16]([C:14]1[S:15][C:11]([CH:7]([N:2]2[CH:6]=[CH:5][N:4]=[CH:3]2)[CH2:8][CH2:9][CH3:10])=[CH:12][CH:13]=1)=[O:18])[CH2:7][CH2:8][CH3:9]
Reactant: CCCC(c1ccc(C(=O)O)s1)n1ccnc1
Agent: Cl
Solvent: CCCCO
Product: CCCCOC(=O)c1ccc(C(CCC)n2ccnc2)s1
Reaction time: 20 h
Yield: 31.2 %

Procedure:
1.2 g of the acid of example 6 is dissolved in 20 ml of butanol and the solution is saturated with hydrochloric-acid gas under ice cooling. After 20 hours, it is concentrated by evaporation, distributed between potassium carbonate solution and ether and the ether phase is separated. After drying and concentration by evaporation of the solvent, it is distilled on the bulb tube. 200 mg of the title compound is obtained. Boiling point: 230° C./0.03 mbar.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([P:10]([O:21][CH2:22][CH3:23])([CH2:12][P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])=[O:11])=[CH:6][C:5]=1[C:24]([CH3:30])([CH3:29])[CH2:25][C:26]([OH:28])=[O:27].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(#N)C>[OH:3][C:4]1[CH:9]=[CH:8][C:7]([P:10]([O:21][CH2:22][CH3:23])([CH2:12][P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])=[O:11])=[CH:6][C:5]=1[C:24]([CH3:30])([CH3:29])[CH2:25][C:26]([O:28][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:27]
Reactant: CCOP(=O)(CP(=O)(OCC)c1ccc(O)c(C(C)(C)CC(=O)O)c1)OCC
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCOP(=O)(CP(=O)(OCC)c1ccc(O)c(C(C)(C)CC(=O)OCc2ccccc2)c1)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
An aqueous KOH solution (0.14 g, 2.5 mmol) was added to a stirring solution of 121 (1.1 g, 2.5 mmol) in acetonitrile (5 mL). After 10 min the solvent was evaporated under reduced pressure and the residue was dried under vacuum for 1 hr. The pale yellow solid was resuspended in DMF (10 mL) followed by the addition of benzylbromide (330 μL, 2.8 eq). The resulting solution was stirred at room temperature for 2 hr. The mixture was diluted with EtOAC (80 mL) and washed with H2O and saturated aqueous NaCl, followed by drying over Na2SO4. The crude product was purified by silica gel chromatography (0-10% methanol in CH2Cl2) on a Biotage™ flash chromatography system, resulting in 122 as a pale yellow liquid (0.64 g, 48%): 1H NMR (400 MHz, CDCl3) δ 1.23 (t, J=7.1, 3H), 1.26 (t, J=7.1, 3H), 1.30 (t, J=7.1, 3H), 1.45 (s, 3H), 1.49 (s, 3H), 2.60 (dd, J=17.4, 20.9, 2H), 3.00 (AB q, J=14.0, 2H), 3.78-3.88 (m, 2H), 3.99-4.15 (m, 4H), 4.93 (s, 2H), 6.75-6.78 (m, 1H), 7.14 (dd, J=2.0, 7.5, 2H), 7.25-7.31 (m, 3H), 7.58 (ddd, J=1.4, 8.0, 11.9, 1H), 7.64 (d, J=13.4, 1H): 31P (162 MHz, CDCl3) δ 21.04 (d, J=4.6, 1 P), 36.00 (d, J=4.6, 1 P).
Reaction SMILES: [O:1]=[C:2]1[C:10](=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][C:13]([NH2:15])=[O:14].O.Cl>CS(C)=O.CCOC(C)=O>[O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][C:13]([NH2:15])=[O:14]
Reactant: NC(=O)CN1C(=O)C(=O)c2ccccc21
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)CN1C(=O)Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 44.2 %

Procedure:
The above 2-(2,3-dioxoindolin-1-yl)acetamide (4.32 g) was redissolved in DMSO (20 mL) and N2H4-xH2O (2.5 mL) was added dropwise over 10 min. After addition, the resulting mixture was stirred for 5 min at rt, then 2 h at 140° C. before cooling to rt. The reaction was quenched with ice (20 mL) and 6 M HCl (8 mL), then stirred for 30 min at rt. Suction filtration gave crude title compound (2.92 g) as a light yellow solid. The product was suspended in EtOAc (120 mL) and H2O (60 mL) was added, followed by 2 M HCl (30 mL). The mixture was separated and suction filtration of aqueous layer afforded the title compound as a light beige solid (1.78 g, 27% over 2 steps) after drying. 1H NMR (400 MHz, DMSO-d6) δ 7.59 (s, 1H, NH), 7.28-7.08 (m, 4H), 6.99 (t, J=7.4 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 4.22 (s, 2H), 3.56 (s, 2H); MS ESI 191.0 [M+H]+, calcd for [C10H10N2O2+H]+ 191.1; MS ESI 174.0 [M−NH2]+, calcd for [C10H10N2O2−NH2]+ 174.1; MS ESI 146.0 [M−CONH2]+, calcd for [C10H10N2O2—CONH2]+ 146.1.
Reaction SMILES: Br[CH2:2][C:3](=[CH2:11])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][CH2:20][CH2:21][OH:22]>O>[CH3:18][O:19][CH2:20][CH2:21][O:22][CH2:2][C:3](=[CH2:11])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: C=C(CBr)C(=O)OC(C)(C)C
Reactant: COCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=C(COCCOC)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-(bromomethyl)acrylate (2.0 g, 9.0 mmol) in 2-methoxyethanol (30 ml) at 0° C. was added, in one portion, potassium carbonate (2.5 g, 18 mmol) and the mixture stirred at 0° C. for 1 hour. The reaction was diluted with distilled water (100 ml) and extracted with dichloromethane (100 ml). The layers were separated and the aqueous layer further extracted with dichloromethane (2×50 ml). The combined organic extracts were dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica by eluting with hexane/ethyl acetate (2:1) to give, after combination and evaporation of appropiate fractions, the title compound as a yellow oil, (1.6 g, 82%). Rf. 0.32 (silica, hexane/ethyl acetate, 2:1). 1H-NMR (300 MHz, CDCl3):=1.50 (s, 9H), 3.42 (s, 3H), 3.56-3.63 (m, 2H), 3.65-3.74 (m, 2H), 4.25 (s, 2H), 5.84 (s, 1H), 6.25 (s, 1H) ppm.