Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:13](Cl)=[O:14])[N:7]2[CH3:12].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]([C@H:33]3[CH2:38][CH2:37][C@H:36]([N:39]4[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)[CH2:35][CH2:34]3)[N:26]3[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[C:27]=23)=[CH:19][C:18]=1[OH:46].C(N(CC)C(C)C)(C)C>ClCCl>[OH:46][C:18]1[CH:19]=[C:20]([C:23]2[N:24]=[C:25]([C@H:33]3[CH2:38][CH2:37][C@H:36]([N:39]4[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)[CH2:35][CH2:34]3)[N:26]3[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[C:27]=23)[CH:21]=[CH:22][C:17]=1[NH:16][C:13]([C:6]1[N:7]([CH3:12])[C:8]2[C:4]([CH:5]=1)=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=2)=[O:14]
Reactant: Cc1nccn2c1c(-c1ccc(N)c(O)c1)nc2[C@H]1CC[C@H](N2CCN(C)CC2)CC1
Reactant: COc1cccc2c1cc(C(=O)Cl)n2C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1cc(C(=O)Nc1ccc(-c3nc([C@H]4CC[C@H](N5CCN(C)CC5)CC4)n4ccnc(C)c34)cc1O)n2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere 4-methoxy-1-methyl-1H-indole-2-carbonyl chloride (described in example 2g) (0.048 mmol, 10.64 mg) was added to a solution of 2-amino-5-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenol (116 mg impure material) and N,N-diisopropylethylamine (0.145 mmol, 24 μl) in dichloromethane at 0° C. The mixture was stirred at room temperature for one hour. Purification by column chromatography (silica gel; gradient of dichloromethane to dichloromethane/methanol 5/1) followed by purification with HPLC (column: X-bridge; eluens acetonitrile/methanol/water with constant 0.003M trifluoroacetic acid). Proper fractions were collected and basified with aqueous sodium carbonate, extracted with dichloromethane, organic layer dried (Na2SO4) and concentrated in vacuo to give N-(2-hydroxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide (7 mg)
Reaction SMILES: [CH:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[OH:17])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][C:28](=[O:30])[CH3:29].[I-].[K+]>CC(C)=O.O>[CH:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[O:17][CH2:27][C:28]([CH3:29])=[O:30])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(C)c(Cc2ccc(C(C)C)cc2)c(O)c1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)COc1cc(C)cc(C)c1Cc1ccc(C(C)C)cc1
Yield: 73 %

Procedure:
A mixed solution of 2-(4-isopropylbenzyl)-3,5-dimethylphenol obtained in Reference Example 148 (1.0 g, 3.93 mmol), potassium carbonate (1.30 g, 9.44 mmol), chloroacetone (436 mg, 4.72 mmol) and potassium iodide (100 mg) in acetone (15 mL) was heated under reflux for 16 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The combined organic layer was washed with a saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 888 mg (yield 73%) of the title compound. Oily matter.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]3[C:11]([CH2:12][CH2:13][CH2:14][CH2:15]3)=[CH:10][C:9]2=[O:17])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH:24]([N:27]([CH:31]([CH3:33])[CH3:32])[CH2:28][CH2:29]Cl)([CH3:26])[CH3:25]>C(O)(C)(C)C>[CH:24]([N:27]([CH:31]([CH3:33])[CH3:32])[CH2:28][CH2:29][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:16]3[C:11]([CH2:12][CH2:13][CH2:14][CH2:15]3)=[CH:10][C:9]2=[O:17])=[CH:6][CH:7]=1)([CH3:26])[CH3:25]
Reactant: O=C1C=C2CCCCC2N1c1ccc(O)cc1
Reactant: CC(C)N(CCCl)C(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)N(CCOc1ccc(N2C(=O)C=C3CCCCC32)cc1)C(C)C
Yield: 75.7 %

Procedure:
22.9 g (0.1 mol) of 1-(4-hydroxyphenyl)-2-oxo-2,4,5,6,7,7a-hexahydro-indole were dissolved, as in Example 4, in a solution of 0.1 mol of potassium tertiary-butoxide in 100 cm3 of tertiary-butanol, and then reacted with 18 g (0.11 mol) of 2-diisopropylamino-1-chloroethane. After conventional treatment of the reaction product, and crystallization from heptane, 27 g (yield 76%) of 1-[4-(2-diisopropyaminoethoxy)-phenyl]-2-oxo-2,4,5,6,7,7a-hexahydro-indole were obtained; m.p. 86° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:18]1[N:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)=[C:20]([CH2:37][CH2:38][CH3:39])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:8][C:9]([C:18]1[N:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[C:20]([CH2:37][CH2:38][CH3:39])[CH:19]=1)([C:10]([F:11])([F:13])[F:12])[C:14]([F:15])([F:16])[F:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ncc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ncc1N1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.9 %

Procedure:
tert-Butyl 4-{6-[2-(benzyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl]-4-propylpyridin-3-yl}piperazine-1-carboxylate (32 mg, 0.0563 mmol) was dissolved in dichloromethane (10 mL). Under ice-cold conditions, trifluoro acetic acid (43 μL, 0.563 mmol) was added and the mixture was stirred at room temperature for 0.5 hours. The reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate under ice-cold conditions, and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (chloroform), and the title compound (27 mg (yield >99%)) was obtained as a yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:50])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[C:24]([C:32]3[CH:42]=[CH:41][C:35]4[O:36][C:37]([F:40])([F:39])[O:38][C:34]=4[CH:33]=3)[CH:23]=2)[C:10]=1[CH2:43][CH2:44][C:45]([O:47]CC)=[O:46])C.[OH-].[Na+].Cl>C(O)C.O>[C:45]([CH2:44][CH2:43][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH3:31])(=[O:29])=[O:30])[CH:25]=[C:24]([C:32]3[CH:42]=[CH:41][C:35]4[O:36][C:37]([F:40])([F:39])[O:38][C:34]=4[CH:33]=3)[CH:23]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:50])=[O:3])([OH:47])=[O:46]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc4c(c3)OC(F)(F)O4)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc3c(c2)OC(F)(F)O3)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.8 %

Procedure:
To a solution of 4-[3-{6-[3-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-5-methanesulfonyl-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (1.0 g) in ethanol (8 mL) was added a solution of NaOH (556 mg) in water (4 mL) and the resulting mixture was stirred at room temperature for 3 h. Then the reaction mixture was diluted with water, acidified with 3 N HCl and extracted into ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oil which was crystallized from ethyl acetate/hexanes mixture to yield the title compound (0.8 g, 87% yield). HRMS calcd for C33H36O10F2S [M+Na]+ 685.1889, observed 685.1892.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([CH2:6][OH:7])[CH2:2]1.Cl[C:9]1[C:18]2[C:13](=[N:14][CH:15]=[CH:16][N:17]=2)[CH:12]=[C:11]([Cl:19])[N:10]=1>>[Cl:19][C:11]1[N:10]=[C:9]([N:1]2[CH2:5][CH2:4][C@@H:3]([CH2:6][OH:7])[CH2:2]2)[C:18]2[C:13](=[N:14][CH:15]=[CH:16][N:17]=2)[CH:12]=1
Reactant: Clc1cc2nccnc2c(Cl)n1
Reactant: OC[C@@H]1CCNC1
Product: OC[C@@H]1CCN(c2nc(Cl)cc3nccnc23)C1

Procedure:
The title compound was prepared according to the procedure of Compound 1 (A) using (R)-pyrrolidin-3-ylmethanol and 5,7-dichloropyrido[4,3-b]pyrazine. MS (m/z): 265 (M+H)+.
Reaction SMILES: [H-].[Na+].O[C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2.S(C1C=CC(C)=CC=1)([O:17][CH2:18][C@@H:19]1[O:21][CH2:20]1)(=O)=O>CN(C=O)C>[O:21]1[CH2:20][C@@H:19]1[CH2:18][O:17][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[CH:13][CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: Oc1cccc2ncccc12
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2c(OC[C@H]3CO3)ccnc2c1
Temperature: 5 °C
Reaction time: 20.5 h
Yield: 16 %

Procedure:
Sodium hydride (60 weight %; 1.79 g; 44.8 mmol) is washed with hexanes (3×10 mL) under an argon blanket. DMF (17 mL) is then added at ambient temperature and the stirred slurry is cooled to 5° C. A solution of 5-hydroxyquinoline (5.00 g; 34.4 mmol) in DMF (65 mL) is added dropwise over 10 minutes. The resulting mixture is allowed to warm to ambient temperature over 1 hour affording a clear, reddish-brown solution. A solution of (R)-(−)-glycidyl tosylate (10.22 g; 44.8 mmol) in DMF (50 mL) is added dropwise over 10 minutes. The resulting mixture is stirred at ambient temperature for 20.5 hours, quenched by the addition of saturated aqueous ammonium chloride (25 mL), poured onto water (750 mL), and extracted with ether (3×375 mL). The combined ether layers are washed with saturated aqueous sodium bicarbonate (2×375 mL), then dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified via silica gel chromatography with gradient elution (50%→60% acetone in hexanes) affording the desired product (1.11 g) as a tan solid. ESMS:MH+ 202.2.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)([CH3:10])[C:8]#[CH:9].[C:18](OCC)(=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].[NH4+].[Cl-]>CCCCCC.CCOCC.CCCCCC.CCOC(C)=O>[CH3:10][C:7]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)([CH3:6])[C:8]#[C:9][C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: C#CC(C)(C)OC1CCCCO1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C(=O)C#CC(C)(C)OC1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (18 mL, of a 1.6 M solution in hexane, 28 mmol) was added to a solution of 3-methyl-3tetrahydropyranyloxy-butyne (3.3 g, 19 mmol) in Et2O, previously cooled at 0° C. The resulting solution was stirred for 30 min at 0° C., then cooled to −78° C. and diethyl oxalate (4.3 mL, 29.4 mmol) was added. The reaction was followed by TLC (hexane/AcOEt 90:10). After ca. 2 h the reaction mixture was poured in a cold aqueous solution of NH4Cl. The aqueous layer was extracted with of Et2O (3×25 mL). The organics were dried over MgSO4, the solvent was removed under reduced pressure and the resulting pale yellow oil was purified by chromatography (silica gel, hexane/AcOEt 90:10) to give ethyl 5-methyl-2-oxo-5-(tetrahydro-2H-pyran-2-yloxy)hex-3-ynoate (2) as a pale yellow liquid. Yield: 2.04 g (40%). 1H-NMR spectrum in CDCl3 (ppm): 5.10 (m, 1H), 4.38 (q, 2H), 4.36 (m, 2H), 3.96 (m, 2H), 3.54 (m, 2H), 1.85 (m, 2H), 1.75 (m, 2H), 1.64 (s, 3H), 1.59 (s, 3H), 1.40 (t, 3H). 13C-NMR spectrum in CDCl3 (ppm): 169.3, 158.7, 101.4, 96.2, 81.6, 70.5, 63.1, 31.5, 29.2, 28.9, 25.2, 19.9, 13.8, 13.8. Selected IR (neat, cm−): 2209, 1741, 1689. MS-APCI calculated for C14H20O5 [M]− 268.13. found 267.96.
Reaction SMILES: CO.[CH:3]1([N:9]2[C:17]3[C:16](=[O:18])[NH:15][C:14]([C:19]4[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27]([O:29]C)=[O:28])=[CH:21][C:20]=4[O:31][CH3:32])=[N:13][C:12]=3[C:11]([CH3:33])=[N:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[OH-].[Na+]>O>[CH:3]1([N:9]2[C:17]3[C:16](=[O:18])[NH:15][C:14]([C:19]4[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])=[CH:21][C:20]=4[O:31][CH3:32])=[N:13][C:12]=3[C:11]([CH3:33])=[N:10]2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)/C=C/c1ccc(-c2nc3c(C)nn(C4CCCCC4)c3c(=O)[nH]2)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(/C=C/C(=O)O)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
To a 1 ml methanol suspension of 45 mg (0.107 mmol) of the compound obtained in Example 226, 1 ml of a 1M aqueous solution of sodium hydroxide was added, and the mixture was stirred at room temperature for 2 hours. Then, the reaction mixture was diluted with water, and the aqueous layer was washed with ether. The aqueous layer was acidified with a 2M aqueous solution of hydrochloric acid, and precipitated solids were collected by filtration to obtain 39 mg (89%) of the captioned compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C@:21]([F:26])([CH3:25])[C:22](O)=[O:23])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]([F:41])([F:40])[CH2:38][NH2:39]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C@:21]([F:26])([CH3:25])[C:22]([NH:39][CH2:38][C:37]([F:41])([F:40])[F:36])=[O:23])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@](F)(C(=O)O)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: NCC(F)(F)F
Product: C[C@](F)(C(=O)NCC(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Yield: 58 %

Procedure:
Using (R)—N—[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-2-fluoro-2-methyl-malonamic acid and 2,2,2-trifluoro-ethylamine, the title compound was prepared in the same manner as described for example 1c. Final chromatography on silica (heptane/ethyl acetate gradient from 5 to 100%) afforded the title compound as white solid (58%). MS: m/e=558(M+H+).
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([O:11][CH3:12])[CH:5]=1.C1COCC1.CO.[OH-].[Li+].Cl>O>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:13])=[O:2])=[CH:5][C:6]=1[O:11][CH3:12]
Reactant: COC(=O)c1ccc(Br)c(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a solution of 4-bromo-3-methoxy-benzoic acid methyl ester (6.875 mmol, 1.676 mL) in a mixture 1:1 of THF/MeOH (15 mL), lithium hydroxide (7.553 mmol, 0.180 g) was added, and the reaction was stirred at RT overnight before distillation of volatiles. The residue was diluted with water, acidified with a solution of HCl (1N), and stirred for 1 hour. The formed precipitate was filtered off, and washed with water and petroleum ether to give 4-bromo-3-methoxy-benzoic acid. Yield: 56%.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][C@@H:13]([CH3:23])[CH2:14][S:15][CH2:16][C:17]2[N:18]=[CH:19][NH:20][C:21]=2[CH3:22])=[NH:11])[N:3]=[CH:2]1.C(NC(N)=N)#N.[Cl-:30].[NH4+]>>[ClH:30].[ClH:30].[ClH:30].[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][C@@H:13]([CH3:23])[CH2:14][S:15][CH2:16][C:17]2[N:18]=[CH:19][NH:20][C:21]=2[CH3:22])=[NH:11])[N:3]=[CH:2]1
Reactant: [Cl-]
Agent: Cc1[nH]cnc1CSC[C@H](C)NC(=N)NCCCc1c[nH]cn1
Agent: N#CNC(=N)N
Agent: [NH4+]
Product: Cl

Procedure:
(S)-(+)-N-[3-(imidazol-4-yl)propyl]-N'-[1-[(5-methyl-imidazol 4-yl)methylthio]-2-propyl]-guanidine ##STR101## prepared by a method analogous to that of Example 39 from 0.58 9 (1.6 mmol) of the previously prepared cyanoguanidine. 0.8 g of a hygroscopic foam composed of equimolar quantities of ammonium chloride and (S)-(+)-N-[3-(imidazol-4-yl)propyl]-N'-[1-[(5-methylimidazol-4-yl)methylthio]-2-propyl]-guanidine trihydrochloride is obtained as residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH3:11].[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:12]([O-:14])=[O:13])[C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH3:11]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(OC)c(C)c1
Solvent: CC(=O)O
Solvent: O
Product: COc1cc([N+](=O)[O-])c(OC)cc1C
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
2,5-dimethoxy toluene (6.0 g) was dissolved in acetic acid (20 mL). To the solution, a solution of fuming nitric acid (d=1.50, 4.32 g) in acetic acid (10 mL) was added dropwise at 40° C. over a period of 5 min. The mixture was stirred at 40° C. for 30 min. The reaction mixture was then allowed to cool to room temperature, which was stirred for another 30 min. Then the reaction mixture was diluted with cold water (300 mL). The resulting precipitate was filtered washed with cold water (100 mL) and dried under reduced pressure to afford the title compound (7.5 g).
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[N+:12]([C:15]1[CH:22]=[CH:21][C:18](CBr)=[CH:17][CH:16]=1)([O-:14])=[O:13].[H-].[Na+].[OH-].[Na+]>C1COCC1.O.C(O)C>[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:3][CH2:2][C:1]([OH:9])=[O:8])=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc([N+](=O)[O-])cc1

Procedure:
Alkylation of diethyl malonate with 4-nitrobenzyl bromide using sodium hydride in THF, followed by ester hydrolysis with sodium hydroxide in water and ethanol, then heating the resulting diacid to its melting point causing decarboxylation gives 3-(4-nitro-phenyl)-propionic acid. Conversion to the acid chloride with thionyl chloride in DCM and coupling with 2-amino-4,6-dimethylpyridine affords N-(4,6-dimethyl-pyridin-2-yl)-3-(4-nitro-phenyl)-propionamide. Amide reduction with borane-dimethylsulfide in THF at reflux, methylation of the resulting amine with methyl iodide and sodium hydride in THF and finally catalytic hydrogenation over Raney nickel in methanol gives the required aniline.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[CH3:19][C:17]1([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=2)[NH:9][CH:8]1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])=[CH:7][CH:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(N)cc1
Solvent: c1ccncc1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(NS(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.6 %

Procedure:
To a solution of 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (100 mg, 0.34 mmol) in pyridine (5 mL) was added benzenesulfonyl chloride (0.05 mL, 0.38 mmol) via syringe with ice cooling. Upon completion of the addition, the resultant mixture was allowed to warm back to room temperature and stir for 24 h. LC-MS showed the reaction was complete. Pyridine was removed in vacuo and the residue was purified by preparative thin layer chromatography to afford 81 mg of 3,3-dimethyl-2-(4-(phenylsulfonamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white solid. Yield: 65%; MS (ESI+APCI) M+1=437.54.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6](=[O:8])[CH3:7].CCN(C(C)C)C(C)C.[CH3:18][Si:19]([CH2:22][CH2:23][O:24][CH2:25]Cl)([CH3:21])[CH3:20].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:18][Si:19]([CH3:21])([CH3:20])[CH2:22][CH2:23][O:24][CH2:25][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6](=[O:8])[CH3:7]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(=O)c1ncc[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1nccn1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(1H-imidazol-2-yl)ethanone (550 mg, 4.99 mmol), 3.18 mmol) in DCM (20 mL) was added DIPEA (1.74 ml, 9.99 mmol) and SEM chloride (0.87 ml dissolved in 5 mL DCM, 4.99 mmol). The resulting mixture was stirred at RT for 1 hr. Saturated aqueous sodium bicarbonate (10 mL) was then added and the aqueous phase was extracted with DCM (3×10 mL extractions). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give the title intermediate as a yellow oil: 1H NMR (500 MHz, CDCl3) delta 0.00 (9H, s), 1.03-0.82 (2H, m), 2.66 (3H, s), 3.66-3.38 (2H, m), 5.76 (2H, s), 7.18 (1H, s), 7.28 (1H, s); LC-MS: m/z=+241.00 (M+H)+.
Reaction SMILES: I[CH2:2][CH2:3][CH:4]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1.CN(C=O)C.CC(C)([O-])C.[K+].CCCCCCC>O>[CH:3]([CH:4]1[CH2:13][CH2:12][C:7]2([O:8][CH2:9][CH2:10][O:11]2)[CH2:6][CH2:5]1)=[CH2:2]
Reactant: ICCC1CCC2(CC1)OCCO2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCCC
Product: C=CC1CCC2(CC1)OCCO2
Temperature: 3 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
233.0 g of the compound (21) and 800 mL of DMF were added to a reactor under nitrogen atmosphere, and stirred at 3° C. under cooling with ice. 92.9 g of potassium t-butoxide (t-BuOK) was added thereto by dividing into 10 portions at a temperature range of from 3 to 10° C. over 2 hours, followed by further stirring at 0° C. for 3 hours. After confirming that the reaction had been completed by GC analysis, the reaction mixture was poured into and mixed with a mixture of 1,500 mL of heptane and 1,500 mL of water at 0° C. The mixture was separated into an organic layer and an aqueous layer by standing still, so as to attain extraction to the organic layer. The resulting organic layer was fractionated and washed with water, followed by drying over anhydrous magnesium sulfate. The resulting organic layer was purified by silica gel column chromatography using heptane as eluent, and the solvent was removed by distillation under reduced pressure. The resulting residue was distilled under reduced pressure to obtain 103.3 g of 8-vinyl-1,4-dioxaspiro[4,5]decane (22) as a colorless transparent liquid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[H-].[Na+].Br[CH2:12][CH2:13][F:14]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:12][CH2:13][F:14]
Reactant: FCCBr
Reactant: Oc1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FCCOc1ccccc1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To a solution of 2-bromophenol (1.0 g, 5.8 mmol) in THF (20 mL) was add NaH (60%) (462 mg, 11.6 mmol). The reaction mixture was stirred at room temperature for 10 min and then 1-bromo-2-fluoroethane (1.5 g, 11.6 mmol) was added and the mixture was irradiated in a microwave reactor at 130° C. for 40 min. The crude mixture was quenched with H2O and the water layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography on silica gel (0-20% DCM in Heptane) to provide the desired compound as a colorless oil (800 mg, 63%).