Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21]C)=[O:20])=[CH:15][CH:14]=2)[OH:11])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)[OH:11])=[CH:23][CH:24]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(CN(O)Cc2ccc(C(=O)OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(CN(O)Cc2ccc(C(=O)O)cc2)cc1

Procedure:
When N,N-bis(p-methoxycarbonylbenzyl)hydroxylamine, prepared in Example 1, is dissolved in an organic solvent and saponified with an aqueous sodium hydroxide solution, th above-named free acid compound is obtained after acidification with a mineral acid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].[CH3:24][S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15]([N:35]2[CH2:34][CH2:33][N:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[S:25][CH3:24])[CH2:37][CH2:36]2)=[O:23])=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2]
Reactant: CSc1ccccc1N1CCNCC1
Reactant: CCOc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Product: CCOc1nc2ccccc2nc1NC(=O)N1CCN(c2ccccc2SC)CC1
Yield: 71.4 %

Procedure:
Phenyl N-(2-ethoxyquinoxalin-3-yl)carbamate and 1-(2-methylthiophenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[N:4]([C:5]([O:13][CH3:14])=[N:6][CH:7]=[C:8]2[O:11][CH3:12])[N:3]=1.[F:15][CH:16]([F:33])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[C:20]=1[S:29](Cl)(=[O:31])=[O:30].N1C=C(C)C=C(C)C=1.Cl>C(#N)C.CS(C)=O>[F:33][CH:16]([F:15])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[C:20]=1[S:29]([NH:1][C:2]1[N:10]=[C:9]2[N:4]([C:5]([O:13][CH3:14])=[N:6][CH:7]=[C:8]2[O:11][CH3:12])[N:3]=1)(=[O:30])=[O:31]
Reactant: O=S(=O)(Cl)c1c(OCC(F)F)cccc1C(F)(F)F
Reactant: COc1cnc(OC)n2nc(N)nc12
Agent: Cc1cncc(C)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: CC#N
Product: COc1cnc(OC)n2nc(NS(=O)(=O)c3c(OCC(F)F)cccc3C(F)(F)F)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
2-Amino-5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidine (19.5 g, 0.10 mol) and 2-(2,2-difluoro-ethoxy)-6-(trifluoromethyl)benzenesulfonyl chloride (32.5 g, 0.10 mol) were combined in acetonitrile (45 mL) and 3,5-lutidine (17 g, 93% technical, ˜0.16 mol) at room temperature. After 10 minutes, DMSO (0.20 g, 0.0026 mol) was added and the reaction slurry was stirred at room temperature for 24 hours. The mixture was then warmed to 48° C. and acidified by the addition of 2 N HCl (100 mL) over 30 minutes, during which the temperature was allowed to fall to ˜38° C. The warm mixture was stirred for one hour, then cooled to 10° C. The precipitated solids were filtered, washed with water (30 mL), washed with methanol (75 mL), and dried under vacuum to afford 44 g of product as a light tan solid assaying at 98 wt % (89% yield).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[CH:8]=1)[CH3:2].[Br:15]Br.O>C(O)(=O)C>[CH2:1]([O:3][CH2:4][CH2:5][S:6][C:7]1[CH:8]=[C:9]([CH3:14])[C:10]([Br:15])=[C:11]([CH3:13])[CH:12]=1)[CH3:2]
Reactant: BrBr
Reactant: CCOCCSc1cc(C)cc(C)c1
Solvent: O
Solvent: CC(=O)O
Product: CCOCCSc1cc(C)c(Br)c(C)c1
Temperature: 25 °C
Yield: 65.1 %

Procedure:
To a solution of 2-[(3,5-dimethylphenyl)thio]ethyl ethyl ether (2.69 g, 12.8 mmol) in acetic acid (60 mL) was slowly added dropwise a solution of bromine (0.68 mL, 13.2 mmol) in acetic acid (30 mL) under stirring at room temperature. The reaction mixture was stirred at the same temperature for 2 hr, poured into cold water, and the mixture was extracted with diethyl ether. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane/ethyl acetate=20/1) to give the title compound (2.41 g, yield 65%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[CH:21]=1)=[O:4].O1CCC[CH2:23]1.C([Li])CCC.CI>CCCCCC>[CH3:23][N:5]([C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][N:9]2[CH:21]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)Nc1cn2cc(Sc3ccccc3)ccc2n1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CI
Product: COC(=O)N(C)c1cn2cc(Sc3ccccc3)ccc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 1.0 g. (0.0033 moles) of 2-(methoxycarbonylamino)-6-(phenylthio) imidazo [1,2-a] pyridine in 35 ml. of tetrahydrofuran under a argon atmosphere is treated dropwise with 1.35 ml. of a 2.45 molar solution of butyllithium in hexane at -20° C. The resultant solution is stirred for 5 minutes and 0.469 g. (0.0033 moles) of methyliodide is added. The reaction mixture is allowed to warm to room temperature and stirred for 30 minutes. The solution is diluted with ice water and the solids are collected by filtration, washed with water and dried. The solid materials is chromatographed on silica gel and eluted with 1:99 methanol in methylene chloride affording 2-[methyl-N-(methoxycarbonyl)amino]-6-(phenylthio) imidazo [1,2-a] pyridine m.p. 147°-149° C.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[CH3:17]I>>[CH3:17][N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCNC1=O
Reactant: CI
Product: CN1CCCC[C@H](NC(=O)OC(C)(C)C)C1=O

Procedure:
(S)-tert-butyl 1-methyl-2-oxoazepan-3-ylcarbamate was prepared from (S)-tert-butyl 2-oxoazepan-3-ylcarbamate (Example 8) and methyl iodide according to the general procedure of Example 9. The crude product was purified by column chromatography, eluting with 50% ethyl acetate/hexanes, to provide compound (2e) in 48% yield.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:28][CH3:29])[C:5]([N:8](COCC[Si](C)(C)C)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])(=[O:11])=[O:10])=[N:6][CH:7]=1.Cl.[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][SH:35]>>[Cl:19][C:13]1[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:5]1[C:4]([O:28][CH3:29])=[N:3][C:2]([S:35][CH2:34][CH2:33][N:32]([CH3:36])[CH3:31])=[CH:7][N:6]=1)(=[O:10])=[O:11]
Reactant: COc1nc(Br)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Reactant: CN(C)CCS
Agent: Cl
Product: COc1nc(SCCN(C)C)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared as for Example 101b using N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-{[2-(trimethylsilanyl)ethoxy]methyl}benzenesulphonamide (Example 55a) (0.3 g) and 2-(dimethylamino)ethanthiol hydrochloride (0.2 g). Yield 0.25 g.
Reaction SMILES: [C:1]1([C:17](OCC2C=CC=CC=2)=[O:18])([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[CH:17]([C:1]1([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:18]
Reactant: O=C(OCc1ccccc1)C1(C(=O)OCc2ccccc2)CCCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: O=CC1(C(=O)OCc2ccccc2)CCCCC1
Temperature: 25 °C
Yield: 79.8 %

Procedure:
A solution of dibenzyl cyclohexane-1,1-dicarboxylate (10.5 g, 30 mmol, from Step A) in 100 mL CH2Cl2 was cooled to −78° C. and a solution of diisobutylaluminum hydride (60 mL, 1 M in CH2Cl2, 60 mmol) was added dropwise. After 3.5 h the mixture was carefully quenched with sat'd ammonium chloride and 1 M HCl. The mixture was warmed to rt and poured into 200 mL water and 200 mmL CH2Cl2. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over magnesium sulfate and concentrated. Flash chromatography (400 g silica, 10/1 hexane/EtOAc) gave 5.9 g (79%) of the desired aldehyde. 1H NMR (500 MHz, CDCl3) δ1.4-1.6 (m, 16), 1.88-1.95 (m, 2H), 2.03-2.12 (m, 2H), 5.2 (s, 2H), 7.30-7.41 (m, 5H), 9.58 (s, 1H).
Reaction SMILES: I[C:2]1[C:10]([I:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4](O)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[I:11][C:10]1[CH:2]=[C:3]([CH:7]=[C:8]([I:12])[CH:9]=1)[CH2:4][OH:5]
Reactant: O=C(O)c1cc(I)cc(I)c1I
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1cc(I)cc(I)c1

Procedure:
Using the procedure of B, Gaux and D. LeHenaff, Bull. Soc. Chem. Fr., 34, 505 (1974), 2,3,5-triiodobenzoic acid (Aldrich) was treated with lithium aluminum hydride to give 3,5-diiodobenzyl alcohol with m.p. of 136.5°-140° (literature 137°). Using the procedure outlined in Example 4, 3,5-diiodobenzyl alcohol was treated with n-hexyl chloroformate giving s in Table I (ND25 =1.5800).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:21][CH2:20][C:19]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:18]=2[Cl:17])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: NCc1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Product: Clc1ccc(CNc2nc(Cl)nc3c2ncn3C2CCCC2)c(Cl)c1

Procedure:
2-Chloro-6-[(2,4-dichlorobenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2,4-dichlorobenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[OH:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+].CO>O1CCOCC1.C(Cl)Cl.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>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([C:24]4[CH:25]=[CH:26][C:21]([OH:20])=[CH:22][CH:23]=4)[CH:3]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:5]=3[CH:6]=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)c1cc(Br)cc2c1cnn2C1CCCC1
Reactant: OB(O)c1ccc(O)cc1
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: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1cc(-c2ccc(O)cc2)cc2c1cnn2C1CCCC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A solution of methyl 6-bromo-1-cyclopentyl-1H-indazole-4-carboxylate (1.5 g, 4.6 mmol), (4-hydroxyphenyl)-boronic acid (0.768 g, 5.56 mmol) and Pd(PPh3)4 (0.536 g, 0.464 mmol) in 1,4-dioxane (15 mL) was purged with argon for 10 min. Then, 2 M Na2CO3 solution (1.77 g, 16.7 mmol) was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After completion of the reaction, water was added to it and extraction was carried out using 5% MeOH in DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford methyl 1-cyclopentyl-6-(4-hydroxyphenyl)-1H-indazole-4-carboxylate (1.1 g, 71%).
Reaction SMILES: [C:1]([C:9]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:10]=1[C:11]([N:13]([CH:20]1[CH2:22][CH2:21]1)[CH2:14][C:15]1[S:16][CH:17]=[CH:18][N:19]=1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O>[CH:20]1([N:13]2[CH:14]([C:15]3[S:16][CH:17]=[CH:18][N:19]=3)[C:1]([OH:8])([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]3[C:10](=[CH:23][CH:24]=[C:25]([O:27][CH3:28])[CH:26]=3)[C:11]2=[O:12])[CH2:21][CH2:22]1
Reactant: COc1ccc(C(=O)N(Cc2nccs2)C2CC2)c(C(=O)c2ccccc2)c1
Solvent: O
Product: COc1ccc2c(c1)C(O)(c1ccccc1)C(c1nccs1)N(C1CC1)C2=O

Procedure:
Compound 16 was prepared by cyclization of amide 15 essentially according to the procedure described in Example I, Step E. No spontaneous elimination of water was observed under these conditions.
Reaction SMILES: Cl.O1CCOCC1.C(OC(N[C@H]([C:20]1[O:25][C:24](=[O:26])[C:23]2[C:27]([CH3:31])=[CH:28][CH:29]=[CH:30][C:22]=2[N:21]=1)C(C)C)=O)(C)(C)C>C1OC=COC1>[CH3:31][C:27]1[C:23]2[C:24](=[O:26])[O:25][CH:20]=[N:21][C:22]=2[CH:30]=[CH:29][CH:28]=1
Reactant: Cc1cccc2nc([C@@H](NC(=O)OC(C)(C)C)C(C)C)oc(=O)c12
Agent: C1=COCCO1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cccc2ncoc(=O)c12
Temperature: 0 °C

Procedure:
66.7 ml of 4N hydrochloric acid-1,4-dioxane solution was added dropwise to a solution of 9.31 g of 2-{1(S)-[(tert-butoxycarbonyl)amino]-2-methylpropyl}-5-methyl-4H-3,1-benzoxazin-4-one in 50 ml of 1,4-dioxene with stirring at 0° C. After stirring at 0° C. for 0.75 hour, the reaction mixture was concentrated. 6.25 g of fluorene-Δ9, α -acetic acid was added to the residue and dissolved in 150 ml of N,N-dimethylformamide. Then, 3.3 ml of N-methylmorpholine, 4.72 g of 1-hydroxybenzotriazole, and 5.91 g of water-soluble carbodiimide hydrochloride were successively added to the resultant solution under ice-cooling. After stirring at room temperature for 18 hours, the reaction solution was condensed, and the residue was purified by a silica gel column chromatography (eluting solution: methylene chloride-ether), followed by recrystallization from chloroform-hexane to give 5.76 g of 2-{1(S)-[(fluorene-Δ9, α -acetyl) amino]-2 -methylpropyl}-5-methyl-4H-3,1-benzoxazin-4-one: mp 223.5°-224.3° C., (see Table 1).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[N:28]=[C:29]([NH:32][C:33](=[O:35])[CH3:34])[S:30][CH:31]=2)=[CH:21][CH:20]=1)[NH:9]C(=O)OC(C)(C)C)(C)(C)C.[ClH:37]>ClCCl.O1CCOCC1>[ClH:37].[NH2:9][C:8]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[N:28]=[C:29]([NH:32][C:33](=[O:35])[CH3:34])[S:30][CH:31]=2)=[CH:21][CH:20]=1)=[NH:7]
Reactant: CC(=O)Nc1nc(CCc2ccc(CNC(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)cs1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(CCc2ccc(CNC(=N)N)cc2)cs1
Reaction time: 15 h

Procedure:
A mixture of di-tert-butyl{[(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}benzyl)amino]methylidene}biscarbamate (20 mg), dichloromethane (2 drops) and 4N hydrogen chloride in 1,4-dioxane (0.5 ml) was stirred for 15 hours. The precipitated crystals were filtered and washed with 1,4-dioxane to give N-(4-{2-[4-({[amino(imino)methyl]amino}methyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide hydrochloride (13 mg).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:28]([CH:29]4[CH2:31][CH2:30]4)=[CH:27][C:16]([C:17]([NH:19][S:20]([CH2:23][CH2:24][O:25]C)(=[O:22])=[O:21])=[O:18])=[CH:15][N:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.B(Br)(Br)Br>ClCCl.C(OCC)(=O)C>[C:1]12([CH2:11][O:12][C:13]3[C:28]([CH:29]4[CH2:31][CH2:30]4)=[CH:27][C:16]([C:17]([NH:19][S:20]([CH2:23][CH2:24][OH:25])(=[O:22])=[O:21])=[O:18])=[CH:15][N:14]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: COCCS(=O)(=O)NC(=O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NS(=O)(=O)CCO)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Reaction time: 0.42 h
Yield: 98.6 %

Procedure:
A solution of 6-(adamantan-1-ylmethoxy)-5-cyclopropyl-N-((2-methoxyethyl)-sulfonyl)nicotinamide (0.19 g, 0.42 mmol) in anhydrous dichloromethane (10 mL) at 0° C. was treated with boron tribromide (0.079 mL, 0.84 mmol) under nitrogen. The reaction mixture was stirred for 25 minutes and then diluted with ethyl acetate (50 mL). The mixture was washed with 1 M aqueous hydrochloric acid solution (2×30 mL), brine (30 mL); dried over anhydrous sodium sulfate; filtered and concentrated in vacuo to provide the title compound (0.18 g, quant.): 1H NMR (300 MHz, DMSO-d6) δ 11.91 (br s, 1H), 8.45 (d, J=2.3 Hz, 1H), 7.70 (d, J=2.3 Hz, 1H), 4.95 (br s, 1H), 3.93 (s, 2H), 3.80-3.73 (m, 2H), 3.65-3.58 (m, 2H), 2.07-1.98 (m, 1H), 1.98-1.90 (m, 3H), 1.73-1.57 (m, 12H), 0.98-0.90 (m, 2H), 0.76-0.70 (m, 2H); MS (ES+) m/z 435.2 (M+1).
Reaction SMILES: [OH-].[K+].C[Si](C)(C)[C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:16])[CH3:15]>O.CO>[C:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:16])[CH3:15])#[CH:5]
Reactant: CC(=O)Nc1ccccc1C#C[Si](C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C#Cc1ccccc1NC(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.8 %

Procedure:
Add a solution of potassium hydroxide (1.62 g, 28.8 mmol) in water (100 mL) dropwise to a rapidly stirred solution of N-(2-trimethylsilanylethynyl-phenyl)-acetamide (4.44 g, 19.2 mmol) in methanol (50 mL) and stir at room temperature for 4 hours. Concentrate, add brine to residue and extract with EtOAc (×3). Dry combined organic layers over MgSO4, concentrate, add CHCl3 and concentrate to get 2.82 g light yellow solid. Purify the residue by flash chromatography on silica gel eluting with 0-30% EtOAc/hexanes to afford the title compound (2.56 g, 84%). MS (IS) 160 (M+1)+.
Reaction SMILES: C(OCC)C.O[CH:7]([CH2:13][C:14]([CH2:17][Si](C)(C)C)=[C:15]=[CH2:16])[CH2:8][CH2:9][C:10](=[O:12])[CH3:11].FC(F)(F)S(O[Si](C)(C)C)(=O)=O.O>C(OCC)(=O)C>[CH3:11][C:10]12[O:12][CH:7]([CH2:8][CH2:9]1)[CH2:13][C:14](=[CH2:17])[C:15]2=[CH2:16]
Reactant: C=C=C(CC(O)CCC(C)=O)C[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOCC
Product: C=C1CC2CCC(C)(O2)C1=C
Temperature: -78 °C
Yield: 94.3 %

Procedure:
1.50 mL of diethyl ether was added to 5-hydroxy-7-trimethylsilanylmethyl-nona-7,8-diene-2-one (86 mg, 0.36 mmol) under nitrogen atmosphere. While stirring at −78° C., trimethylsilyl trifluoromethanesulfonate (TMSOTf; 64.7 μL, 0.36 mmol) was added. While stirring the reaction mixture, the reaction temperature was slowly increased to room temperature for 3 hours. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was completed, H2O was added. After stirring for about 5 minutes, the reaction mixture was diluted with ethyl acetate (EtOAc) and washed with water and saturated brine. The organic layer was separated from the reaction mixture and dried with anhydrous magnesium sulfate (MgSO4). The solvent was removed under reduced pressure and the remaining material was purified with column chromatography (EtOAc/n-hexane=1/5) to obtain 51 mg of the product (94%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([N:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:9]2=[O:24])=[N:5][C:4]=1[CH3:25]>ClCCl.C(OCC)(=O)C>[CH3:25][C:4]1[N:5]=[C:6]([N:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:9]2=[O:24])[S:7][C:3]=1[CH:2]=[O:1]
Reactant: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
To a solution of 1-(5-(hydroxymethyl)-4-methylthiazol-2-yl)-3-(4-(trifluoromethyl)benzyl)imidazolidin-2-one (0.40 g, 1.07 mmol) in dichloromethane (50 mL) was added Dess-Mertin periodinane (0.60 g, 1.40 mmol). The reaction mixture was stirred for 6 hours at ambient temperature, and then diluted with ethyl acetate, washed with 10% sodium thiosulfate solution, saturated sodium bicarbonate solution and brine. The organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford the title compound in 80% yield (0.32 g): MS (ES+) m/z 370.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH2:8].[CH2:12]=O.[ClH:14]>O>[ClH:14].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:12][NH:8][CH2:7][CH2:6]2
Reactant: C=O
Reactant: COc1cccc(CCN)c1
Agent: Cl
Solvent: O
Product: COc1ccc2c(c1)CCNC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
To a stirred suspension of 3-methoxyphenethylamine (50.4 g, 0.33 mol. 1.0 eq) in water (40 mL) was added 37% aqueous formaldehyde solution (27.5 mL, 1.1 eq) and stirring continued for 20 min. Concentrated HCl (80 mL) was added and the mixture heated at reflux for 1 h. After cooling to room temperature the mixture was evaporated to dryness. The residue was recrystallised from acetone, affording the desired product as a white solid (60.1 g, 90%) which was used without further purification for the next step. MH+ 164.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:21]=[O:22])C>>[CH3:11][C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:21]=[O:22])=[CH:3][CH:4]=1)([CH3:12])[CH2:9][CH3:10]
Reactant: CCC(C)(C)c1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: CCC(C)(C)c1ccc(C=O)cc1
Yield: 90 %

Procedure:
The title compound was synthesized in analogy to example S1-A using 1-bromo-4-(1,1-dimethylpropyl)-benzene (synthesized in analogy to a procedure described in J. Chem. Res. Miniprint., 1997, 12, 2701-2733) (250 mg, 1.10 mmol), nBuLi (825 μl, 1.6M solution in hexane, 1.32 mmol) and DMF (427 μl, 5.50 mmol). The isolated residue was purified by flash column chromatography (1:9 ether:pentane) to give 4-(1,1-dimethylpropyl)-benzaldehyde (175 mg, 90%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): 9.99 (s, 1H), 7.82 (d, J=8.5 Hz, 2H), 7.50 (d, J=8.5 Hz, 2H), 1.69 (q, J=7.5 Hz, 2H), 1.32 (s, 6H), 0.68 (t, J=7.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].C(=O)(O)[O-].[Na+].Cl[CH2:16][C:17]([O:19][CH3:20])=[O:18]>>[CH3:20][O:19][C:17](=[O:18])[CH2:16][NH:5][C:4]1[CH:3]=[C:2]([F:1])[CH:8]=[C:7]([F:9])[CH:6]=1
Reactant: COC(=O)CCl
Reactant: Nc1cc(F)cc(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)CNc1cc(F)cc(F)c1
Reaction time: 60 h

Procedure:
A suspension of 3,5-difluoroaniline (15.0 g) and sodium bicarbonate (19.5 g) in methyl chloroacetate (15.2 ml) was stirred at 80°-90° under nitrogen for 60 h. More sodium bicarbonate (4.88 g) and methyl chloroacetate (5.1 ml) were added, and the suspension was stirred at 80°-90° for a further 24 h. Work up according to the method of Intermediate 11 gave a solid (16 g) which was recrystallised from chloroform (10 ml) and n-hexane (120 ml) to give the title compound (8.34 g), m.p. 75°-77°.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[CH3:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([CH:33]=1)[C:30](O)=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:30](=[O:31])[C:29]3[CH:33]=[C:25]([CH3:24])[CH:26]=[N:27][CH:28]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: Cc1cncc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1c2ccc(NC(=O)c3cncc(C)c3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (0.10 g) with 5-methyl nicotinic acid (0.13 g) under the agency of HATU (0.18 g) and N,N-diisopropylethylamine (0.28 ml) in dichloromethane (2 ml) was performed according to the method described in example 11.