Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[Cl:15])[C:4](=O)[CH3:5])#[N:2].O.[NH2:17][NH2:18].Cl>C1(C)C=CC=CC=1.C(O)(=O)C>[NH2:2][C:1]1[NH:18][N:17]=[C:4]([CH3:5])[C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[Cl:15]
Reactant: NN
Reactant: COc1ccc(C(C#N)C(C)=O)c(Cl)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2c(C)n[nH]c2N)c(Cl)c1
Temperature: 50 °C
Reaction time: 7 h

Procedure:
Under argon gas atmosphere, to a solution of the compound prepared in Example 1 (38.7 g) in toluene, acetic acid (14.5 mL) and 60% aqueous solution of hydrazine hydrate (17.7 mL) were sequentially added at 10 to 30° C. of internal temperature. The mixture was stirred for 7 hours at 45 to 55° C. of internal temperature. To the reaction solution cooled to 10 to 30° C. of internal temperature, 2 mol/L hydrochloric acid was added and then the mixture was separated. The aqueous layer was adjusted to pH 6.5 to 7.5 by adding 25 wt % sodium hydroxide. Isopropyl acetate (216 mL) was added to the adjusted aqueous layer. The separated organic layer was concentrated under reduced pressure. The residue was heated, and n-heptane was added. The solution was cooled to 10 to 30° C. of internal temperature. After the crystal was precipitated, the solution was stirred for 30 minutes. Furthermore, n-heptane was added to the solution, and the mixture was stirred for 1 hour. The precipitated crystal was collected by filtration, dried under reduced pressure for 14 hours or more at about 50° C. to give the title compound having the following physical data (35.5 g (94.8 area %); quantitative value: 61% (2 processes)).
Reaction SMILES: [Cl:1][CH:2]([F:9])[C:3]([F:8])([F:7])[C:4](Cl)=[O:5].[CH2:10]([O:12][C:13](=[O:35])[CH:14]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH2:34])[CH:29]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:11]>ClCCl.N1C=CC=CC=1>[CH2:10]([O:12][C:13](=[O:35])[CH:14]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:4](=[O:5])[C:3]([F:8])([F:7])[CH:2]([Cl:1])[F:9])[CH:29]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:11]
Reactant: CCCCCCCCCCCCC(Oc1cccc(N)c1)C(=O)OCC
Reactant: O=C(Cl)C(F)(F)C(F)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCC(Oc1cccc(NC(=O)C(F)(F)C(F)Cl)c1)C(=O)OCC

Procedure:
An amount of 63.35 g (0.35 mol) of 3-chloro-2,2,3-trifluoro-propionyl chloride is added dropwise in 30 min to a solution of 109 g (0.3 mol) of 2-(m-aminophenoxy)-myristic acid ethyl ester in 450 ml of dichloromethane and 48 ml of pyridine. A slight reflux is observed. The mixture is then refluxed for 2 h. Subsequently, the reaction mixture is washed first with 1N hydrochloric acid and next with water until neutral. The solvent is removed by evaporation.
Reaction SMILES: [CH3:1][C:2]1[C:9]([OH:10])=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=[C:6]([CH3:15])[C:3]=1[CH2:4]Br.[CH:16]1([P:22]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)([SH:24])=[S:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([P:22]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)([S:24][CH2:4][C:3]2[C:6]([CH3:15])=[CH:7][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[C:9]([OH:10])[C:2]=2[CH3:1])=[S:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: S=P(S)(C1CCCCC1)C1CCCCC1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CBr
Product: Cc1cc(C(C)(C)C)c(O)c(C)c1CSP(=S)(C1CCCCC1)C1CCCCC1

Procedure:
2,6-Dimethyl-3-hydroxy-4-t-butylbenzyl bromide was reacted with the ammonium salt of dicyclohexylphosphinodithioic acid to obtain 2,6-dimethyl-3-hydroxy-4-t-butylbenzyl dicyclohexylphosphinodithioate, m.p. 113°-116° C, which on testing lasted 150 hours longer than the control. The total number of hours required to reach failure was 1.3 times that of the control.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]2[CH3:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32](Cl)=[O:33]>C(Cl)Cl>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=3)=[O:33])[CH2:14][C@@H:13]2[CH3:18])(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1ccccn1
Reactant: C[C@H]1CNCCN1S(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(C(=O)c2ccccn2)CCN1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 72.6 %

Procedure:
To a solution of (2S)-1-[(4-chlorophenyl)sulfonyl]-2-methylpiperazine hydrochloride (Description 4) (200 mg, 0.728 mmol) in DCM (8 mL) was added triethylamine (0.172 ml, 1.237 mmol) and the reaction was cooled to 0° C. and stirred under argon. 2-pyridinecarbonyl chloride (155 mg, 0.873 mmol) was added portionwise and the reaction was slowly allowed to warm to rt, stirring continued for 18 hours. The sample was evaporated, the crude residue was purified by silica chromatography (5 g silica SPE), (eluting a gradient from 20-90% ethyl acetate in hexane) and the product containing fractions were concentrated. The product was then dissolved in 1,4-dioxane (2 ml) to this was added 1M ethereal HCl (4 ml) the sample was evaporated and then triturated in diethyl ether until solid. The solid was dried under vacuum at 40° C. for 18 hours to yield the title compound as a white solid (110 mg)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[SH:10].Br[CH:12]([CH2:17][CH2:18][CH2:19][Br:20])[C:13](OC)=[O:14].O>CN(C)C=O>[Br:20][CH2:19][CH2:18][CH2:17][CH:12]1[C:13](=[O:14])[NH:1][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=2[S:10]1
Reactant: Cc1cc(N)c(S)cc1C
Reactant: COC(=O)C(Br)CCCBr
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(cc1C)SC(CCCBr)C(=O)N2
Yield: 69.3 %

Procedure:
To a solution of 3.06 g of 2-amino-4,5-dimethylthiophenol in 50 ml of dimethylformamide was added 5.48 g of methyl 2,5-dibromovalerate at room temperature with stirring. The mixture was stirred for 14 hours, poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The residue was washed with a mixture of ether and hexane to obtain 4.35 g (69.3%) of 2-(3-bromopropyl)-6,7-dimethyl-2H-1,4-benzothiazin-3(4H)-one as crystals. Recrystallization from methanol gave prisms, m.p. 151°-153° C.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:13]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]2([CH3:29])[CH3:28])(=[O:15])[CH3:14].[CH2:30](O)[CH:31]([OH:33])[CH3:32].C1(C)C=CC=CC=1>O>[CH3:14][C:13]1([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]3([CH3:29])[CH3:28])[O:33][CH:31]([CH3:32])[CH2:30][O:15]1
Reactant: CC(O)CO
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1COC(C)(c2ccc3c(c2)C(C)(C)CCC3(C)C)O1
Temperature: 110 °C

Procedure:
p-Toluenesulphonic acid monohydrate (2 g) is added to a suspension of 120 g (0.5 mol) of 6-acetyl-1,1,4,4-tetra-methyl-tetralin, 120 g (1.6 mol) of propylene glycol and 600 ml of toluene. The mixture is heated to 110° C. The reaction water is removed azeotropically within 5 hours. After cooling to room temperature the mixture is adjusted to pH 7.5 to 8 by the addition of 10% potassium hydroxide in ethanol. Thereupon, the mixture is filtered. The solvent is evaporated and the residual liquid is distilled under a vacuum, whereby there separate as the main product 123 g of 2.4-dimethyl-2-(1,1,4,4-tetramethyl-tetralin-6-yl)-1,3-dioxolane as a mixture of the boiling point is 112° C. at 0.5 mmHg; nD20 =1.5130. The product has a strong woody, animalic odour.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].O.[I:19]Cl.C1(C)C=CC=CC=1>Cl>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[C:15]([I:19])[CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: ClI
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc(O)c(I)c1)OCC
Yield: 98.13 %

Procedure:
To stirred solution of racemic ethyl 2-ethoxy-3-(4-hydroxyphenyl)propionate of the formula (13a) (20 g) obtained according to the procedure described in step (v) above and dimineralised water (100 ml), ICl (13.6 g, 4.4 ml) in HCl (80 ml) was added dropwise at room temperature for 30 min. The reaction mixture was heated to 75° C. to 80° C. for 20 h. The progress of the reaction was monitored by TLC. After completion of the reaction, toluene (200 ml) was added to the reaction mixture and extracted with dimineralised water. Organic extracts were concentrated to yield the crude compound. The crude compound was purified by column chromatography using 3% ethyl acetate in pet. ether to yield the title compound (10.3 g, 98.13%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](I)[CH3:24].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([C:14]([O:16][CH2:23][CH3:24])=[O:15])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2ccc(Cl)cc2)cc1C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2)oc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.1 %

Procedure:
A mixture of 5-(4-chlorophenyl)-2-methyl-3-furancarboxylic acid (4.7 g), potassium carbonate (2.8 g) and ethyl iodide (3.7 g) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane) to give the title compound (5.0 g, 95%) as a yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:17](=[O:18])[CH:16]3[C:11](=[CH:12][CH2:13][CH2:14][CH2:15]3)[C:10]2=[O:19])=[CH:4][C:3]=1[S:20][C:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1.[CH3:27][OH:28].C(N(CC)CC)C>C(OC)(=O)C>[CH3:27][O:28][C:24]([C:21]1([S:20][C:3]2[CH:4]=[C:5]([N:9]3[C:17](=[O:18])[CH:16]4[C:11](=[CH:12][CH2:13][CH2:14][CH2:15]4)[C:10]3=[O:19])[C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[CH2:23][CH2:22]1)=[O:25]
Reactant: O=C1C2=CCCCC2C(=O)N1c1cc(SC2(C(=O)Cl)CC2)c(Cl)cc1F
Reactant: CO
Solvent: COC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C1(Sc2cc(N3C(=O)C4=CCCCC4C3=O)c(F)cc2Cl)CC1
Temperature: 25 °C

Procedure:
While stirring at room temperature, a solution of 1 g of 1-[2-chloro-4-fluoro-5-(1,2,3,4,5,6-hexahydro-1,3-dioxo-isoindolyl)-phenylthio]-cyclopropanecarboxylic acid chloride obtained in accordance with Example P9 in 10 ml of methyl acetate is added dropwise to a solution of 10 ml of methanol and 0.5 ml of triethylamine in 10 ml of methyl acetate. After stirring for 3 hours at room temperature, the resulting triethylamine hydrochloride is filtered off and the filtrate is concentrated by evaporation, yielding 0.9 g of 1-[2-chloro-4-fluoro-5-(1,2,3,4,5,6-hexahydro-1,3-dioxo-isoindolyl)-phenylthio]-cyclopropanecarboxylic acid methyl ester having a melting point of from +142° to +144° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]([CH3:22])[CH3:21])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:17][CH2:18][OH:19])([CH2:15][CH3:16])[O:12][CH2:13][CH2:14][C:7]2=1.[F:23][C:24]1[CH:29]=[C:28](B(O)O)[CH:27]=[CH:26][C:25]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:15]([C:11]1([CH2:17][CH2:18][OH:19])[C:8]2[NH:9][C:10]3[C:6]([C:7]=2[CH2:14][CH2:13][O:12]1)=[CH:5][C:4]([CH:20]([CH3:22])[CH3:21])=[CH:3][C:2]=3[C:28]1[CH:27]=[CH:26][C:25]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[C:24]([F:23])[CH:29]=1)[CH3:16]
Reactant: OB(O)c1ccc(-c2ccccc2)c(F)c1
Reactant: CCC1(CCO)OCCc2c1[nH]c1c(Br)cc(C(C)C)cc21
Product: CCC1(CCO)OCCc2c1[nH]c1c(-c3ccc(-c4ccccc4)c(F)c3)cc(C(C)C)cc21

Procedure:
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 2-fluorobiphenyl-4-boronic acid in step 1.F.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]3[CH:20]=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=3)=[N:17][CH:18]=1)[N:9]=[C:8]([C:26](OCC)=[O:27])[C:7]2=S.[NH:32]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[OH:40])[NH2:33].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.C(OCC)(=O)C>[Cl:1][C:2]1[C:11]2[N:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[CH:20]=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=4)=[N:17][CH:18]=3)[N:9]=[C:8]3[C:26](=[O:27])[N:32]([C@@H:34]4[CH2:39][CH2:38][CH2:37][CH2:36][C@H:35]4[OH:40])[N:33]=[C:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nn(Cc2ccc(-c3ccc(C)nc3)nc2)c2c(Cl)cccc2c1=S
Reactant: NNC1CCCCC1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1ccc(-c2ccc(Cn3nc4c(=O)n([C@@H]5CCCC[C@H]5O)nc-4c4cccc(Cl)c43)cn2)cn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Ethyl 8-chloro-1-[(6′-methyl-2,3′-bipyridin-5-yl)methyl]-4-thioxo-1,4-dihydrocinnoline-3-carboxylate (26 mg, 0.0058 mmol), (±)-2-hydrazinylcyclohexanol (19 mg, 0.14 mmol, 2.5 equiv) and potassium carbonate (24 mg, 0.17 mmol, 3 equiv) were combined in dimethoxyethane (1 mL) and placed into an oil bath preheated to 90° C. for 90 minutes. The mixture was cooled to ambient temperature, diluted with ethyl acetate and washed once with water and brine. The organic layer was dried sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 90:10; chloroform:methanol), providing the titled compound as a deep red solid: 1H-NMR (400 MHz, CDCl3) δ 9.02 (1H, br s), 8.56 (1H, s), 8.21 (1H, d, J=9.1 Hz), 8.16 (1H, d, J=10.9 Hz), 7.65 (2H, d, J=7.5 Hz), 7.56 (1H, d, J=9.2 Hz), 7.43 (2H, t, J=7.5 Hz), 7.27-7.21 (1H, m), 6.33 (2H, s), 4.34-4.25 (1H, m), 4.11-4.02 (1H, m), 2.6 (3H, s), 2.26-2.17 (1H, m), 2.07-2.00 (1H, m), 1.92-1.79 (2H, m), 1.68-1.56 (2H, m), 1.52-1.39 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 501.1812 [(M+H)+; calculated for C27H25ClN6O2: 501.1800].
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4]1.[NH2:14][C:15]1[C:23]([Cl:24])=[CH:22][C:18]([C:19](O)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[NH2:14][C:15]1[C:23]([Cl:24])=[CH:22][C:18]([C:19]([NH:1][CH2:2][CH:3]2[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4]2)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CCOC(=O)N1CCOC(CN)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)N1CCOC(CNC(=O)c2cc(Cl)c(N)cc2OC)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.3 %

Procedure:
To a solution of 2-aminomethyl-4-ethoxycarbonylmorpholine (5.8 g) in dichloromethane (100 ml), 4-amino-5-chloro-2-methoxybenzoic acid (5.0 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.2 g) are added, and the resulting mixture is stirred at 25° C. for 4 hours. The reaction mixture is washed successively with water, aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure. The residue is dissolved in chloroform and chromatographed on silica gel. The eluate with chloroform is discarded, and the subsequent eluates with methanol-chloroform (1:9) are pooled and evaporated to give the title compound (7.5 g) as an oil.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16][CH3:17])[CH2:10][CH2:9]1)(C)(C)C.[ClH:19].CO>>[ClH:19].[ClH:19].[CH3:17][S:16][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]1
Reactant: CSCCN1CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Product: CSCCN1CCC(N)CC1
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
[1-(2-Methylsulfanyl-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.35 g, 1.0 mmol) was dissolved in HCl/Methanol (2.5M, 4 mL) and stirred for 1.5 h at 40° C. After evaporation of the solvent and drying under high vacuum, 1-(2-methylsulfanyl-ethyl)-piperidin-4-ylamine dihydrochloride was obtained as an off-white solid (0.22 g, 100%); MS: m/e=175.5 (M+H+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][CH2:21][CH2:22][CH2:23][OH:24].[Cl:25][C:26]1[C:35]2[C:30](=[CH:31][C:32](O)=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][N:27]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Cl:25][C:26]1[C:35]2[C:30](=[CH:31][C:32]([O:24][CH2:23][CH2:22][CH2:21][Cl:20])=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][N:27]=1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Reactant: OCCCCl
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Cl)ncnc2cc1OCCCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
Triphenylphosphine (2.6 g, 10.1 mmol) and 3-chloropropanol (0.69 ml, 8.2 mmol) were added to a suspension of 4-chloro-7-hydroxy-6-methoxyquinazoline (1.65 g, 7.8 mmol) in dichloromethane (100 ml) under argon. The flask was placed in a water bath at 20° C. and di-tertbutyl azodicarboxylate (2.30 g, 10.1 mmol) added portion wise over a few minutes. The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated and the solution loaded directly onto a silica chromatography column. Elution with ethyl acetate:petroleum ether (3:7), yielded 4-chloro-7-(3-chloropropoxy)-6-methoxyquinazoline (2.0 g, 91% yield):
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8]C)=[C:6]([Cl:10])[CH:5]=[CH:4][N:3]=1.P(Cl)(Cl)(Cl)=O.COC1C(=O)C=CNC=1Br>>[Br:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:10])[CH:5]=[CH:4][N:3]=1
Reactant: COc1c(Cl)ccnc1Br
Agent: COc1c(Br)[nH]ccc1=O
Solvent: O=P(Cl)(Cl)Cl
Product: Oc1c(Cl)ccnc1Br
Temperature: 20 °C

Procedure:
2-bromo-4-chloro-3-methoxypyridine. Phosphorus oxychloride (10 eq.) and 3-methoxy-2-bromo-4(1H)-pyridone (1 eq.) are stirred at 90° C. for 18 h, concentrated in vacuo, and cooled to 20° C. The residue is treated with ice water and adjusted to pH 12 with 40% NaOH, and the product is extracted into DCM. The residue obtained on evaporation of the combined extracts is distilled at reduced pressure to afford the title compound.
Reaction SMILES: C1(C2C=CC=CC=2)C=CC([C:7]([OH:19])([CH2:17]Cl)[CH2:8]C2C=CC(Cl)=CC=2Cl)=CC=1.[H-].[Na+].[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1>C(#N)C>[N:28]1([CH2:17][CH:7]([OH:19])[CH3:8])[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: c1c[nH]cn1
Reactant: OC(CCl)(Cc1ccc(Cl)cc1Cl)c1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(O)Cn1ccnc1
Temperature: 80 °C

Procedure:
A solution of 39.15 g (0.1 mol) of 2-(4-biphenylyl)-3-chloro-1-(2,4-dichlorophenyl)-propan-2-ol in 300 ml of acetonitrile is added dropwise to a suspension of 3.6 g (0.12 mol) of sodium hydride and 8.2 g (0.12 mol) of imidazole in 200 ml of acetonitrile. After heating to 80° C. for 3 hours, the cooled reaction mixture is filtered and the crystal mass is washed with water and with acetonitrile. 32.5 g (77% of theory) of 2-(4-biphenylyl)-1-(2,4-dichlorophenyl)-3-(imidazol-1-yl-propan-2-ol of melting point 168° C. are obtained.
Reaction SMILES: [CH2:1](OC(C1(CCCCSC)CCC1)=O)[CH3:2].[CH2:16]([O:18][C:19]([C:21]1([CH2:25][CH2:26][CH2:27][CH2:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH2:24][CH2:23][CH2:22]1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1([CH2:25][CH2:26][CH2:27][CH2:28][S:29]([CH3:32])(=[O:30])=[O:31])[CH2:24][CH2:23][CH:22]1[CH2:1][CH3:2])=[O:20])[CH3:17]
Reactant: CCOC(=O)C1(CCCCSC)CCC1
Reactant: CCOC(=O)C1(CCCCS(C)(=O)=O)CCC1
Product: CCOC(=O)C1(CCCCS(C)(=O)=O)CCC1CC
Yield: 92 %

Procedure:
Using the general procedure described in example 46, starting with 1-[4-(methylthio)butyl]cyclobutanecarboxylic acid ethyl ester, 1-[4-(methylsulfonyl)-butyl]cyclobutanecarboxylic acid ethyl ester was prepared in 92% yield as a colorless oil. HR MS: Obs. mass, 262.1231. Calcd. mass, 262.1238, M+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=3[N:7]=[CH:6]2)[CH2:3][CH2:2]1.Cl[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23]>>[CH:1]1([CH2:4][N:5]2[C:13]3[C:12](=[O:14])[N:11]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])[C:10](=[O:15])[N:9]([CH3:16])[C:8]=3[N:7]=[CH:6]2)[CH2:2][CH2:3]1
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2CC1CC1
Reactant: CC(C)(O)CCCCCl
Product: Cn1c(=O)n(CCCCC(C)(C)O)c(=O)c2c1ncn2CC1CC1

Procedure:
The title compound was prepared by using 7-cyclopropylmethyl-3-methylxanthine and 1-chloro-5-hydroxy-5-methylhexane as starting materials.
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C([O-])(C)C.[K+].[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[N+:29]([O-:31])=[O:30])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CS(C)=O>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]2[CH2:7][C@H:28]2[N+:29]([O-:31])=[O:30])=[CH:23][CH:22]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)[O-]
Reactant: O=[N+]([O-])/C=C/c1ccc(OCc2ccccc2)cc1
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 25.3 %

Procedure:
Trimethylsulfoxonium iodide (0.62 g, 2.82 mmol) was added in portions to a solution of t-BuOK (0.32 g, 2.82 mmol) in dry DMSO (5 mL) After 10 min a solution of 1-(benzyloxy)-4-[(E)-2-nitrovinyl]benzene (0.60 g, 2.35 mmol) in DMSO (5 mL) was transferred via canula and the mixture was stirred at room temperature for 6 h. The reaction was poured over water (10 mL) and extracted with Et2O (3×10 mL); the organic layers were washed with brine (2×15 mL), dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the residual orange oil was purified by column chromatography on silica gel (5% EtOAc/hexanes) affording 0.16 g of 1-(benzyloxy)-4-[(trans)-2-nitrocyclopropyl]benzene [Rf=0.5 (20% EtOAc/hexanes), white solid, 26% yield].
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][O:7][Si:8]([CH3:11])([CH3:10])[CH3:9])=[C:4]([CH3:14])[CH:3]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][C:4]1[CH:3]=[C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:13]=[CH:12][C:5]=1[CH2:6][O:7][Si:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: Cc1cc(Br)ccc1CO[Si](C)(C)C
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Cc1cc(C#C[Si](C)(C)C)ccc1CO[Si](C)(C)C
Temperature: 70 °C
Yield: 65.1 %

Procedure:
Using General Procedure D; (4-bromo-2-methyl-benzyloxy)-trimethylsilane (Intermediate 134, 550.0 mg, 2.01 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (38.0 mg, 0.20 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (1.05 g, 10.6 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (142.0 mg, 0.20 mmol). The resulting reaction mixture was heated to 70° C. for 5 days. The title compound (380.0 mg, 65%) was isolated by chromatography (0-2% EtOAc-hexanes) as an orange oil.
Reaction SMILES: [NH2:1][N:2]1[C:6](=[O:7])[C:5]([CH2:10][CH3:11])([CH2:8][CH3:9])[NH:4][C:3]1=[O:12].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:1][N:2]2[C:6](=[O:7])[C:5]([CH2:10][CH3:11])([CH2:8][CH3:9])[NH:4][C:3]2=[O:12])=[O:22])=[CH:16][CH:15]=1
Reactant: CCC1(CC)NC(=O)N(N)C1=O
Reactant: O=C=Nc1ccc(Br)cc1
Solvent: Cc1ccccc1
Product: CCC1(CC)NC(=O)N(NC(=O)Nc2ccc(Br)cc2)C1=O
Temperature: 100 °C

Procedure:
A mixture of 3-amino-5,5-diethylimidazolidine-2,4-dione CAS 1007-61-0 (70 mg, 0.4 mmol), 4-bromophenylisocyanate CAS 2493-02-9 (80 mg, 0.4 mmol) in toluene (5 mL) was heated at 100° C. for 8 h. Upon cooling the reaction to ambient temperature, Compound 1 separated as a white solid, which was collected by filtration and dried under high vacuum.