Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[OH:17])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18](OBr)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26]>>[CH2:1]([C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:12][C:11]=1[OH:17])=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCCCCCCOBr
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1O
Product: CC(C)CCCCCCCOc1ccc(C(=O)Cc2ccccc2)c(O)c1

Procedure:
The 2-hydroxy-4-isodecyloxyphenyl benzyl ketone was prepared by alkylation of 2,4-dihydroxyphenyl benzyl ketone with isodecyloxy bromide as follows:
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1.[C:18]([O-])([O-])=O.[Na+].[Na+].F[B-](F)(F)F.C[O+](C)C.O>C(Cl)Cl>[CH2:11]([O:10][C:8]([N:4]1[CH2:3][C:2]([O:1][CH3:18])=[N:7][CH2:6][CH2:5]1)=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: O=C([O-])[O-]
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC1=NCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Yield: 94.7 %

Procedure:
A solution of benzyl 3-oxopiperazine-1-carboxylate (20.50 g, 10.67 mmol) in CH2Cl2 (100 ml) was cooled to 0° C. and treated with Na2CO3 (23.0 g, 217 mmol) for 10 minutes. Neat trimethyloxonium tetrafluoroborate (5.50 g, 37.2 mmol) was added in one portion, then the reaction is allowed to warm to room temperature for 6 hours. The reaction was poured into water (100 ml), and the layers were separated. The aqueous layer was re-extracted aqueous with 50 ml CH2Cl2 and the combined organic layers were washed with brine (100 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to yield 5-methoxy-3,6-dihydro-2H-pyrazine-1-carboxylic acid benzyl ester (2.51 g, 95%) as an oil. LCMS (Table 1, Method a) Rt=3.00 min, m/z 249.24 (M+H)+−; 1H NMR (400 MHz, DMSO-d6) δ 7.36 (m, 5H), 5.16 (s, 2H), 3.96 (s, 2H), 3.68 (s, 3H), 3.54 (s, 2H), 3.47 (m, 2H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:23]([F:26])([F:25])[F:24])=[N:15][C:16]([C:17](=[O:22])N(OC)C)=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:27]1([Mg]Br)[CH2:31][CH2:30][CH2:29][CH2:28]1.[Cl-].[NH4+]>O1CCCC1.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:23]([F:25])([F:24])[F:26])=[N:15][C:16]([C:17]([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:22])=[C:10]2[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CON(C)C(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)OC(C)(C)C)CC2
Reactant: Br[Mg]C1CCCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)C3CCCC3)c2C1
Yield: 32.7 %

Procedure:
1-(Methoxy-methyl-carbamoyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester 27e (0.3 g, 0.79 mmol) was dissolved in 20 mL of tetrahydrofuran under stirring, and then cyclopentylmagnesium bromide (0.79 mL, 1.58 mmol) was added dropwise to the solution at 0° C. The reaction mixture was stirred at 0° C. for 3 hours and monitored by thin layer chromatography until the disappearance of the starting materials. 50 mL of saturated ammonium chloride and 10 mL of saturated brine were added. The crude mixture was extracted with ethyl acetate (100 mL×3), and then the combined organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 1-cyclopentanecarbonyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester 28a (0.1 g, yield 30%) as a yellow oil.
Reaction SMILES: COC(=O)C1C=CC(NC(=O)C2C=CC(O)=C(N)C=2)=NC=1.[CH3:22][O:23][C:24](=[O:44])[C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]2[CH:35]=[CH:36][C:37]3[O:42][CH2:41][CH2:40][NH:39][C:38]=3[CH:43]=2)=[O:33])=[N:27][CH:26]=1.[Cl:45][C:46]1[CH:47]=[CH:48][C:49]([O:56][CH3:57])=[C:50]([S:52](Cl)(=[O:54])=[O:53])[CH:51]=1>>[CH3:22][O:23][C:24](=[O:44])[C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]2[CH:35]=[CH:36][C:37]3[O:42][CH2:41][CH2:40][N:39]([S:52]([C:50]4[CH:51]=[C:46]([Cl:45])[CH:47]=[CH:48][C:49]=4[O:56][CH3:57])(=[O:53])=[O:54])[C:38]=3[CH:43]=2)=[O:33])=[N:27][CH:26]=1
Reactant: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)NCCO3)nc1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Agent: COC(=O)c1ccc(NC(=O)c2ccc(O)c(N)c2)nc1
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCO3)nc1

Procedure:
6-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-nicotinic acid, MS (ISP): m/e=502.1 (M−H), was prepared as described for example 14, steps 1 to 8. Step 4 was performed using 6-amino-nicotinic acid methyl ester, yielding 6-(4-benzyloxy-3-nitro-benzoylamino)-nicotinic acid methyl ester, which was reduced to 6-(3-amino-4-hydroxy-benzoylamino)-nicotinic acid methyl ester in step 5 and cyclized to 6-[(3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl)-amino]-nicotinic acid methyl ester in step 6. Step 7 was performed using 5-chloro-2-methoxy-benzenesulfonyl chloride and yielded 6-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-nicotinic acid methyl ester, which was hydrolyzed in step 8.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH2:53][CH2:54][O:55][CH2:56][CH3:57])[CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH2:56]([O:55][CH2:54][CH2:53][O:52][C:48]1[CH:47]=[C:46]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)[CH:51]=[CH:50][CH:49]=1)[CH3:57]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCOCCOc1cccc(OB([O-])[O-])c1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCOCCOc1cccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.5 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) was added toluene/ethanol/water (20/1/1, 13.9 ml) and then were added 3-(2-ethoxyethoxy)phenyl borate (145 mg) and potassium carbonate (176 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (27 mg), and the mixture was refluxed for 10 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-[3-(2-ethoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 115) (152 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.ON1C2N=CC=CC=2N=N1.[C:40]([O:44][C:45]([N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)=[O:46])([CH3:43])([CH3:42])[CH3:41]>ClCCl.O>[C:40]([O:44][C:45]([N:47]1[CH2:52][CH2:51][N:50]([C:6](=[O:8])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[CH2:49][CH2:48]1)=[O:46])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
4-Fluorobenzoic acid (6b) (7 g, 50 mmol) was dissolved in dichloromethane (100 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (10.5 g, 55 mmol), triethylamine (7.7 mL, 55 mmol) and 1-hydroxy-7-azabenzotriazole (HOAt) (7.5 g, 55 mmol) were added successively, stirred for half an hour at room temperature, and then 1-tertbutoxycarbonylpiperazine (6a) (10.2 g, 55 mmol) was added and stirred overnight. On the next day, water was added to quench the reaction. The reaction solution was washed successively with 50 mL saturated sodium bicarbonate solution and saturated sodium chloride solution for three times, the organic phases were concentrated to give 1-tertbutoxycarbonyl-4-(4-fluorobenzoyl)piperazine (6c), 14.8 g white solid (yield 96%). ESI-MS m/z calculated for: 308.15. found: 309.25 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:9]([O:11][CH3:12])=[O:10].[N:18]([O-:20])=[O:19].[Na+].C(O)(=O)C.[N+]([O-])(O)=O>O>[CH3:17][O:16][C:15]1[C:6]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=1
Reactant: COC(=O)c1ccc(OC)c(OCCCCl)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: O=[N+]([O-])O
Product: COC(=O)c1cc(OCCCCl)c(OC)cc1[N+](=O)[O-]
Temperature: 40 °C
Yield: 961.5 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer and a dropping funnel were placed 10.1 g (38.7 mmol) of methyl 3-(3-chloropropoxy)-4-methoxybenzoate (purity: 99%) obtained in Reference Example III-11, 0.27 g (3.87 mmol) of sodium nitrite, and 12.5 mL of acetic acid. The resulting mixture was heated to 40° C. under stirring. To the reaction mixture was dropwise added slowly 16.2 g (154.8 mmol) of nitric acid (60 wt. %), and the mixture was heated at the same temperature for 5 hours. After the reaction was complete, 20 mL of water was added to the reaction mixture, and the aqueous mixture was cooled to 20° C., precipitating a crystalline product. The crystalline product was collected by filtration, washed successively with 30 mL of water and 30 mL of n-heptane, and dried under reduced pressure, to give 11.3 g (isolated yield: 95.0%, purity: 99% in terms of area percentage determined by high performance liquid chromatography) of methyl 4-methoxy-5-(3-chloropropoxy)-2-nitrobenzoate as a white crystalline product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH2:23])[CH:19]=3)[N:14]=1)[CH2:9][CH2:8]2.[CH3:24][N:25]([CH3:30])[CH2:26][C:27](O)=[O:28]>>[CH3:24][N:25]([CH3:30])[CH2:26][C:27]([NH:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([NH:12][CH:10]1[C:11]3[C:7](=[CH:6][CH:5]=[CH:4][C:3]=3[O:2][CH3:1])[CH2:8][CH2:9]1)[CH:22]=[CH:21]2)=[O:28]
Reactant: CN(C)CC(=O)O
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)CN(C)C)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method 14 described in example 119 from rac-N2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example 172) and N,N-dimethylglycine; MS: m/e=391.4 (M+H+).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH:7]2[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[O:8]2)[N:6]=1.CCCCCC.C([Li])CCC.CN(C)[CH:27]=[O:28].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH3:12][C:9]1([CH3:13])[O:8][CH:7]([C:5]2[N:6]=[C:2]([CH:27]=[O:28])[S:3][CH:4]=2)[CH2:11][O:10]1
Reactant: CC1(C)OCC(c2csc(Br)n2)O1
Reactant: CN(C)C=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)OCC(c2csc(C=O)n2)O1
Temperature: -70 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
To a solution of 2-bromo-4-(2,2-dimethyl-1,3-dioxolan-4-yl)-1,3-thiazole (3.00 g) in tetrahydrofuran (40 mL) was slowly added a 1.6M n-butyllithium hexane solution (7.8 mL) at −70° C. under a nitrogen atmosphere. The reaction mixture was stirred at −70° C. for 1 hr, and N,N-dimethylformamide (2.50 g) was added. The reaction mixture was warmed to room temperature, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (1.03 g, yield 42%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:5, volume ratio).
Reaction SMILES: [OH-].[Na+].[CH3:3]Cl.[CH3:5][O:6][CH:7]([NH:9][C:10](=[O:12])[CH3:11])[CH3:8]>>[CH3:5][O:6][CH:7]([N:9]([CH3:3])[C:10](=[O:12])[CH3:11])[CH3:8]
Reactant: COC(C)NC(C)=O
Reactant: CCl
Agent: [Na+]
Agent: [OH-]
Product: COC(C)N(C)C(C)=O
Reaction time: 3 h

Procedure:
1,800 g of 50% strength sodium hydroxide solution, 900 g of sodium hydroxide in the form of flakes and 300 g of methyl chloride are initially introduced into a pressure kettle provided with an anchor stirrer. 1,760 g of N-α-methoxyethyl-acetamide and 1,000 g of methyl chloride are uniformly metered in over a period of 3 hours. After a further 3 hours, the kettle is depressurized and the contents are degassed by passing in nitrogen. The reaction product with a lower specific gravity is separated from the inorganic constituents with a higher specific gravity in a centrifuge, and the reaction product is decanted off and distilled in vacuo. 1,804 g (91% of theory) of N-α-methoxyethyl-N-methylacetamide of boiling point1.0 48° are obtained.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].Cl.[NH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(C(C)C)CC)(C)C>ClCCl>[C:13]([O:12][C:10]([CH2:9][NH:8][C:2](=[O:3])[O:4][CH2:5][Cl:6])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C(Cl)OCCl
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)OCCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of chloromethyl chloroformate (1.69 g) in dichloromethane (5 ml) was added dropwise with stirring to an ice-cold solution of tert-butyl glycinate, hydrochloride (2.0 g) and diisopropylethylamine (3.7 g) in dichloromethane (20 ml). After stirring for a further 2 hours at room temperature, the mixture was extracted with ice-cold 0.5 M hydrochloric acid followed by water and aqueous sodium bicarbonate. Drying over magnesium sulfate and evaporation in vacuo gave the title compound as a colourless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].[NH2:10][C:11](N)=[O:12].Cl>O.C(O)(=O)C>[OH:8][C:7]1[CH:6]=[C:5]([CH3:9])[CH:4]=[CH:3][C:2]=1[NH:1][C:11]([NH2:10])=[O:12]
Reactant: NC(N)=O
Reactant: Cc1ccc(N)c(O)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(NC(N)=O)c(O)c1
Yield: 86 %

Procedure:
To 13 ml of water, there were added 5.00 g (40.7 mmol) of 6-amino-m-cresol, 9.76 g of (162.6 mmol) of urea, 4 ml of conc. hydrochloric acid and 0.8 ml of a mixture (1:1 (v:v)) of conc. hydrochloric acid and glacial acetic acid, followed by heating under reflux for 1.5 hours. After cooling, 20 ml of water was added. The crystals thus precipitated were filtered and dried to thereby give 5.81 g (35.0 mmol) of N-(2-hydroxy-4-methylphenyl)urea as dark brown crystals. The yield was 86%. After recrystallizing from acetonitrile, 2.00 g of N-(2-hydroxy-4-methylphenyl)urea was obtained as pale purple crystals. The recovering yield was 34%.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:18][CH2:17][C:12]2(OCC[O:13]2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O.[Cl-].[Na+]>C(OC(C)C)(C)C>[CH2:1]([O:8][CH:9]1[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COC2CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)OC(C)C
Product: O=C1CCC(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.5 %

Procedure:
294 g of 8-benzyloxy-1,4-dioxaspiro[4.5]decane were dissolved in 1400 ml of diisopropyl ether, and 580 ml of four molar hydrochloric acid were added. After 20 hours' stirring at room temperature, 300 ml of water and 180 ml of saturated sodium chloride solution were added, and stirring was carried out for a further four hours. The phases were separated, and the aqueous phase was neutralized with solid sodium hydrogen carbonate and extracted repeatedly with diisopropyl ether. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Distillation under a high vacuum yielded 231 g of 4-benzyloxycyclohexanone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9][CH2:10][CH2:11]OC=S.[CH2:15](Br)C#C.CN(C)CCN>C(O)C.C1COCC1.C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9][CH2:10][C:11]#[CH:15]
Reactant: C#CCBr
Reactant: Cc1ccc(Br)c(SCCOC=S)c1
Agent: CN(C)CCN
Solvent: C1CCOC1
Solvent: CCO
Product: C#CCSc1cc(C)ccc1Br
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 94.2 %

Procedure:
To a solution of (2-bromo-5-methylphenylthio)ethoxymethane-1-thione (80.23 g, 275 mmol) in ethanol-THF (2/1) (420 ml), a solution of propargyl bromide (49.13 g, 413 mmol) in ethanol (140 ml) was slowly added dropwise in an ice bath and stirred in an ice bath for 20 minutes. Furthermore, while keeping the mixture in the ice bath, a solution of N,N-dimethylethylenediamine (48.48 g, 550 mmol) in ethanol (275 ml) was added dropwise over 15 minutes. The mixture was kept in the ice bath for 20 minutes, and removed from the ice bath and left at room temperature for 1 hour, followed by further stirring at 30° C. in an oil bath for 2 hours. To a separatory funnel that contained 2N aqueous hydrochloric acid (600 ml) and hexane (500 ml), the reaction mixture was added and extracted as it was. The aqueous phase was extracted with hexane (300 ml), and the organic phase combined was washed with 1N aqueous hydrochloric acid (200 ml). Then, after washing with water (200 ml×2 times), it was dried on magnesium sulfate. The solvent was evaporated to obtain 1-bromo-4-methyl-2-(prop-2-inylthio)benzene (62.35 g, 259 mmol). The yield was 94%.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:29][CH2:28][C@H:27]([O:30][Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])[CH2:26]3)=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.CO.C(Cl)Cl>[CH:38]([Si:31]([CH:32]([CH3:34])[CH3:33])([CH:35]([CH3:37])[CH3:36])[O:30][C@H:27]1[CH2:28][CH2:29][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26]1)([CH3:40])[CH3:39]
Reactant: CC(C)[Si](O[C@H]1CCN(c2nnc3ccc(F)cn23)C1)(C(C)C)C(C)C
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CC(C)[Si](O[C@H]1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1)(C(C)C)C(C)C
Temperature: 60 °C
Reaction time: 4 h
Yield: 23.1 %

Procedure:
To a solution of Intermediate A (104 mg, 0.640 mmol) in DMF (2 mL) was added NaH (60% in oil, 70 mg, 1.74 mmol) and the mixture stirred at RT for 20 min, before Intermediate 26b (220 mg, 0.582 mmol) was added. This mixture was stirred thermally at 60° C. for 4 h, then at 60° C. in the microwave for 3 h. The cooled reaction mixture was applied to an SCX-2 cartridge (10 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM gave the title compound as a yellow gum (70 mg, 23%). LCMS (Method 1): Rt 2.89, m/z 522 [MH+].
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].N[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[CH:15][N:16]([C:18]([N:20]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH3:21])=[O:19])[CH:17]=2)=[CH:9][CH:8]=1>O1CCOCC1>[CH:22]1([N:20]([CH3:21])[C:18]([N:16]2[CH:17]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([NH:4][S:1](=[O:3])(=[O:2])[NH2:5])=[CH:8][CH:9]=3)[N:14]=[CH:15]2)=[O:19])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CN(C(=O)n1cnc(-c2ccc(N)cc2)c1)C1CCCCC1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: CN(C(=O)n1cnc(-c2ccc(NS(N)(=O)=O)cc2)c1)C1CCCCC1
Yield: 6 %

Procedure:
Sulfamide (0.089 g, 0.922 mmol) was added to a stirred suspension of 4-(4-aminophenyl)-N-cyclohexyl-N-methyl-1H-imidazole-1-carboxamide (0.250 g, 0.838 mmol) in dioxane (2 mL) at room temperature. The suspension was heated at reflux for 4 h to give a clear solution, whereupon more sulfamide (0.089 g, 0.922 mmol) was added and the mixture was heated at reflux for a further 2.5 h. The solvent was removed and the brown residue was purified by chromatography (silica, dichloromethane/methanol, 1%, 2%, 5%). Homogenous fractions were pooled and evaporated. The residue was triturated with ethyl acetate and the colourless solid that formed was removed by filtration. The filtrate was evaporated and purified again by preparative TLC (silica, dichloromethane/10% methanol). The product was extracted from the silica with a mixture of ethyl acetate/10% methanol. Evaporation of the solvent gave a clear oil, that was triturated with a mixture of ethyl acetate and methanol to give the product as an off-white solid (19 mg, 6%).
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:44]=[C:43]([S:45]([CH3:48])(=[O:47])=[O:46])[C:42]([F:49])=[CH:41][C:40]=1[CH3:50]>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:39]1[CH:44]=[C:43]([S:45]([CH3:48])(=[O:47])=[O:46])[C:42]([F:49])=[CH:41][C:40]=1[CH3:50])([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1cc(F)c(S(C)(=O)=O)cc1Br
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: Cc1cc(F)c(S(C)(=O)=O)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 1-bromo-4-fluoro-5-methanesulfonyl-2-methyl-benzene (Ger. Offen. 2000; DE 19919349), the title compound was obtained as a brown oil after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[S:6])[CH2:2][C:3]([CH3:5])=O.[OH-].[K+].[CH3:16]I.O>C(O)C>[CH3:5][C:3]([CH3:16])=[CH:2][C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[S:6]
Reactant: CC(=O)CC(=S)Nc1ccccc1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)=CC(=S)Nc1ccccc1
Temperature: 20 °C

Procedure:
11.6 g of thioacetoacetanilide and then a solution of 3.4 g of potassium hydroxide in 35 ml of ethanol were added to 60 ml of ethanol and the mixture was stirred for an hour at 20° C. 8.5 g of methyl iodide were added thereto and the mixture was poured into 300 ml of water. The precipitate formed was recovered by vacuum filtration, and was dissolved in chloroform. The chloroform solution was dried and concentrated to dryness under reduced pressure to obtain 12g of 3-methylthio-crotonanilide melting at 175° C. After crystallization from acetone, the melting point was 178° C.