Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=1.C(N(C(C)C)C(C)C)C.CCOC(C)=O>CN(C=O)C>[Cl:8][C:6]1[N:5]=[C:4]([CH3:9])[N:3]=[C:2]([NH:19][CH2:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[N:7]=1
Reactant: Cc1nc(Cl)nc(Cl)n1
Reactant: COc1ccc(CN)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2nc(C)nc(Cl)n2)cc1
Yield: 94.7 %

Procedure:
To a solution of 2,4-dichloro-6-methyl-1,3,5-triazine (190 g, 1159 mmol) in DMF (1500 mL) was added (4-methoxyphenyl)methanamine (159 g, 1159 mmol) slowly in 15 min while the temperature was controlled below 20° C. This was followed by the addition of N-ethyl-N-isopropylpropan-2-amine (222 mL, 1274 mmol) slowly over 15 min. After the completion of the reaction, EtOAc (2000 mL) was added and the mixture was washed with dilute brine (200 mL saturated NaCl plus 500 mL water), water (500 mL), saturated NH4Cl (250 mL), and finally water (250 mL). The organic layer was concentrated to afford 4-chloro-N-(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine as a solid (290.5 g, 1097 mmol, 95% yield). m/z 265.2 (M+H).
Reaction SMILES: N[C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[O:4][CH:5]([CH:12]1[O:17][CH2:16][C:15](=[O:18])[N:14]([CH3:19])[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N([O-])=[O:25].[Na+]>OS(O)(=O)=O.O>[OH:25][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[O:4][CH:5]([CH:12]1[O:17][CH2:16][C:15](=[O:18])[N:14]([CH3:19])[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN1CC(C(Oc2ccccc2N)c2ccccc2)OCC1=O
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CN1CC(C(Oc2ccccc2O)c2ccccc2)OCC1=O
Reaction time: 0.33 h
Yield: 59.8 %

Procedure:
10 g of 2-[α-(2-amino-phenoxy)-benzyl]-4-methyl-morpholin-5-one was dissolved at 0° C. in 32 ml of 35% H2SO4. At this temperature slow addition was made of 2.76 g of NaNO2 dissolved in 40 ml of H2O and the mixture was kept under stirring in cold conditions for 20 minutes. Still at 0° C. there was added 120 g of Cu(NO3)2 dissolved in 1000 ml of H2O and 4.2 g of Cu2O. After 5 minutes extraction was performed in cold conditions with ethyl acetate; the organic phase was washed to neutrality with a saturated aqueous solution of NaCl, dehydrated with sodium sulphate and evaporated to dryness. There was obtained a yellow oil which was separated by column chromatography on silica gel (phase: ethyl acetate/cyclohexane 2:1). There was obtained 6 g (Yield 60%) of 2-[α-(2-hydroxy-phenoxy)-benzyl]-4-methyl-morpholin-5 -one.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[C:12](=[O:13])[N:11]2[C:14]([CH2:24][N:25]([CH3:33])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[N:16]=[C:10]2[N:9]([CH2:34][C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])[CH:8]=1)=[O:6])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH2:49]([N:51]=[C:52]=[O:53])[CH3:50]>C1COCC1>[CH:1]([O:4][C:5]([C:7]1[C:12](=[O:13])[N:11]2[C:14]([CH2:24][N:25]([CH3:33])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:15]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:52]([NH:51][CH2:49][CH3:50])=[O:53])=[CH:21][CH:22]=3)[N:16]=[C:10]2[N:9]([CH2:34][C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])[CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1cn(Cc2c(F)cccc2F)c2nc(-c3ccc(N)cc3)c(CN(C)Cc3ccccc3)n2c1=O
Reactant: CCN=C=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCNC(=O)Nc1ccc(-c2nc3n(Cc4c(F)cccc4F)cc(C(=O)OC(C)C)c(=O)n3c2CN(C)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a solution of the compound obtained in Example 32 (1.37 g, 2.40 mmol) in THF (3 ml) is added pyridine (0.5 ml) and ethyl isocyanate (0.38 ml, 4.8 mmol). Then the mixture is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure to give the residue, which triturated with isopropyl ether to afford a crystalline solid, which is recrystallized from chloroform-isopropyl ether to afford pale yellow crystals (1.20 g, 78%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([Cl:37])[CH:35]=2)[C:10]2([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[NH:12][CH:11]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:9]1=[O:38])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Li+].I[CH3:42]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([Cl:37])[CH:35]=2)[C:10]2([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[N:12]([CH3:42])[CH:11]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:9]1=[O:38])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: Cc1ccccc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)N(C(=O)OC(C)(C)C)c1cc(Cl)ccc12
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccccc1C1N(C)C(=O)CC(c2cccc(Cl)c2)C12C(=O)N(C(=O)OC(C)(C)C)c1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.6 %

Procedure:
To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (0.25 g, 0.45 mmol) in N,N-dimethyl-formamide (20 mL) at 0° C. was added LiH (90 mg, 11.2 mmol) (Aldrich), followed by the addition of iodomethane (0.39 g, 2.74 mmol). The reaction mixture was warmed up to room temperature and stirred at room temperature for 3 h. The mixture was diluted with ethyl acetate, and then washed with saturated NH4Cl solution. The aqueous layer was extracted with ethyl acetate and the combined organic layer was dried over MgSO4. The solvent was removed and the residue was purified by chromatography (EtOAc:hexanes=1:2) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-1′-methyl-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (Yield 0.20 g, 77%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][Cl:28]>CC(=O)CC.C(OCC)(=O)C>[Cl:28][CH2:27][CH2:26][CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(OCCCCl)cc2)cc1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
The product from Example 10A (4.50 g, 19.7 mmol), K2CO3 (4.0 g, 29.6 mmol) and 3-bromochloropropane (3.88 g, 24.6 mmol) in 2-butanone (100 mL) were heated at reflux for 24 hours. The mixture was allowed to cool to ambient temperature and then diluted with ethyl acetate (200 mL). The mixture was washed with water (2×100 mL) and brine (100 mL) and the remaining organic layer was dried over MgSO4 and filtered. The filtrate was evaporated under reduced pressure to provide the title compound as an off-white solid (5.5 g, 92% yield).
Reaction SMILES: O1CCCC1.B.[C:7]([C:11]1[CH:16]=[CH:15][C:14]([CH:17](O)[C:18]2[C:19]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[C:20]3[C:28](=[CH:29][C:30]=2[CH:31]([CH3:33])[CH3:32])[O:27][C:23]2([CH2:26][CH2:25][CH2:24]2)[CH2:22][C:21]3=[O:34])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8]>N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.CO>[C:7]([C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18]2[C:19]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[C:20]3[C:28](=[CH:29][C:30]=2[CH:31]([CH3:33])[CH3:32])[O:27][C:23]2([CH2:26][CH2:25][CH2:24]2)[CH2:22][C@@H:21]3[OH:34])=[CH:15][CH:16]=1)([CH3:9])([CH3:10])[CH3:8]
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(C)(C)C)cc1)C(=O)CC1(CCC1)O2
Agent: B
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1Cc1ccc(C(C)(C)C)cc1)[C@@H](O)CC1(CCC1)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.5 %

Procedure:
Under argon, 1.4 mg (0.009 mmol) of (1R,2S)-1-aminoindan-2-ol are dissolved in 2 ml of abs. tetrahydrofuran, 66 μl (0.37 mmol) of borane/,N-diethylaniline complex are added and the mixture is stirred at room temperature for 30 min. After this time, 45 mg (0.092 mmol) of 6-[(4-tert-butylphenyl)(fluoro)methyl]-5-(4-fluorophenyl)-7-isopropylspiro[chromen-2,1′-cyclobutan]-4(3H)-one (Example 55A), dissolved in 2 ml of abs. tetrahydrofuran, are added at room temperature over a period of 10 min, and the mixture is then stirred at room temperature for 15 h. 2 ml of methanol are added and the mixture is stirred for 15 min and then concentrated to dryness. The residue is taken up in ethyl acetate and washed twice with 1 N hydrochloric acid, twice with saturated sodium bicarbonate solution and twice with saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and concentrated. The crude product is purified by thick-layer chromatography (mobile phase: cyclohexane/ethyl acetate 10:1). This gives 33.5 mg (77% of theory, 80% ee) of the title compound. Chromatographic separation of 60 mg of Example 36 on a chiral phase [column: Chiralpak AD-H, 250×20 mm; mobile phase: isopropanol/isohexane 3:97; flow rate: 15 ml/min; 24° C.; detection: 260 nm] gives 45 mg of the title compound having an ee of >99%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[NH2:34][CH2:35][CH2:36][CH2:37][OH:38].C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9]([NH:34][CH2:35][CH2:36][CH2:37][OH:38])(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: NCCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)NCCCO)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
Under an atmosphere of argon protective gas, 5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonyl chloride (25 mg, 51 μmol) was dissolved in absolute THF (1.5 ml), 3-aminopropanol (11 μl, 152 μmol; 3 eq.) and triethylamine (5.1 mg, 51 μmol; 1 eq.) were added at room temperature and the mixture was stirred overnight. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Kromasil C-18, 5 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave a colorless amorphous solid (18 mg, 67% of theory).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[N:3][CH:2]=1.Br.[CH3:16][C:17]1([CH3:23])[NH:21][C:20]([NH2:22])=[N:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:16][C:17]1([CH3:23])[CH2:18][N:19]2[C:9](=[O:11])[CH:8]=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][N:3]=3)[N:22]=[C:20]2[NH:21]1
Reactant: CC1(C)CN=C(N)N1
Reactant: CCOC(=O)CC(=O)c1ccncn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC1(C)Cn2c(nc(-c3ccncn3)cc2=O)N1

Procedure:
A mixture containing 2.0 g (10.3 mmol) of ethyl 3-(4-pyrimidinyl)-3-oxopropionate, 2.0 g (10.3 mmol) of 5,5-dimethyl-4,5-dihydro-1H-imidazol-2-ylamine hydrobromide and 2.85 g (20.6 mmol) of potassium carbonate in 15 ml of methanol were heated at reflux temperature during 18 h.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([N:12]3[CH:20]([CH2:21][CH3:22])[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([Cl:23])[CH:18]=4)[C:13]3=[O:24])[C:6]=2[CH2:5][CH2:4][CH2:3]1.CCN(CC)CC.[CH3:32][S:33](Cl)(=[O:35])=[O:34].Cl>C(Cl)Cl.O1CCOCC1>[Cl:23][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:24])[N:12]([C:7]1[C:6]3[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[C:11]=3[CH:10]=[N:9][CH:8]=1)[CH:20]2[CH2:21][CH3:22]
Reactant: CS(=O)(=O)Cl
Reactant: CCC1c2cc(Cl)ccc2C(=O)N1c1cncc2c1CCCC2N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCC1c2cc(Cl)ccc2C(=O)N1c1cncc2c1CCCC2NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
To a solution of 2-(8-amino-5,6,7,8-tetrahydro-isoquinolin-4-yl)-5-chloro-3-ethyl-2,3-dihydro-isoindol-1-one (511.5 mg, 1.5 mmol) in DCM (15 mL) was added Et3N (3 mmol) and methanesulfonyl chloride (228 mg, 2 mmol) at 0° C. The resulting reaction mixture was stirred at room temperature for 1 hour before it was poured into 1 N HCl in dioxane (15 mL) and washed with EtOAc (15 mL×2). After the organic layer was decanted, the aqueous layer was basified to pH>8 with satd. aq. NaHCO3 solution. After extracted with EtOAc (20 mL×2), the combined organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give the title compound (228 mg, 62%) as a mixture of four diastereomers. MS: 420.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CC(C)=O.O>[CH2:9]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1ccccc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Brc1ccccc1OCc1ccccc1
Yield: 100 %

Procedure:
To a stirring solution of 2-bromophenol (10.0 g, 57.8 mmol), and benzyl bromide (9.9 g, 57.8 mmol) in acetone (150 mL) was added K2CO3 (12.0 g, 86.7 mmol). After stirring at reflux for 4 h, the mixture was portioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a colorless oil (15.2 g, 57.8 mmol). 1HNMR (400 MHz, CDCl3) δ7.62 (m, 1H), 7.54 (m, 2H), 7.45 (m, 2H), 7.37 (m, 1H), 7.28 (m, 1H), 6.98 (m, 1H), 6.91 (m, 1H), 5.17 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[CH:22][CH:21]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[C:16][CH2:17][CH2:18][OH:19])[CH:10]=2)[N:3]=1.[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH:27]([F:29])[F:28])=[CH:24][CH:25]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:10]=2)[N:3]=1
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(C#CCCO)c2)N=C1N
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(CCCCO)c2)N=C1N
Yield: 61 %

Procedure:
A mixture of a solution of 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-hydroxybut-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one (0.26 g, 0.65 mmol) in ethanol and 5% palladium on charcoal (26 mg) was placed on a Paar hydrogenator at 40 psi hydrogen for 8 hrs. The reaction mixture was filtered through a celite pad. The filtrate was concentrated in vacuo. The resultant residue was purified by flash chromatography on silica gel, 5% methanol/ ethyl acetate as eluent, to give the title product as a white solid, 0.16 g (61% yield), mp 63-66° C.; 1H NMR (DMSO-d6) δ 1.4 ((2H, 2H); 1.5 (m, 1 H); 2.5 (2H, under DMSO peak) 2.95 (s, 3 H); 3.3 (q, 2 H); 4.3 (t, 1 H); 6.6 (b, 2H); 7.1 (m, 3H); 7.15 (t, 2F); 7.2 (m, 3 H); 7.4 (d, 2 H); MS [(+)ESI] m/z=404 [M−H]+.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([C:7]1[CH:12]=[C:11]([SH:13])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:6])[CH3:5].C([O:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25]Br)C.O>CC(C)=O>[CH3:6][C:4]([C:7]1[CH:12]=[C:11]([S:13][CH2:25][CH2:24][CH2:23][C:22]([OH:27])=[O:21])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:3])[CH3:5]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)c1cc(SCCCC(=O)O)cc(C(C)(C)C)c1O
Reaction time: 1.5 h

Procedure:
Potassium hydroxide flakes (2.52g, 0.045 mole) were added to a clear solution of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (3.57 g. 0.0165 mole) and ethyl-4-bromo-butyrate (3.23 g, 0.0165 mole) in acetone (10 ml). Water (20 ml) was added and the solution stirred for 1.5 hours, the solvent removed on a rotary evaporator and water (50 ml) added, and the mixture was extracted with ethyl ether (3×75 ml). The aqueous layer was acidified with concentrated hydrochloric acid, extraced with ethyl ether (2×50 ml), the combined organic extracts were washed with water (50 ml), dried over sodium sulfate, filtered and the solvents removed, leaving an oil, which was purified by chromatography on silica, recrystallized from ethyl ether/Skellysolve B, filtered and the product dried in vacuo at room temperature for 12 hours, m.p. ca. 112°-113.5° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([S:13]([CH2:16][CH2:17][CH2:18][CH2:19][Cl:20])(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.Cl.[NH2:23][C:24]1[C:39]([Cl:40])=[CH:38][C:27]([C:28]([NH:30][CH2:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[O:29])=[C:26]([O:41][CH3:42])[CH:25]=1.O>CN(C)C=O>[ClH:20].[NH2:23][C:24]1[C:39]([Cl:40])=[CH:38][C:27]([C:28]([NH:30][CH2:31][CH:32]2[CH2:33][CH2:34][N:35]([CH2:19][CH2:18][CH2:17][CH2:16][S:13]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)(=[O:14])=[O:15])[CH2:36][CH2:37]2)=[O:29])=[C:26]([O:41][CH3:42])[CH:25]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=S(=O)(CCCCCl)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCS(=O)(=O)c2ccccc2)CC1
Reaction time: 7.5 h
Yield: 13.4 %

Procedure:
Potassium carbonate (0.87 g) and 4-phenylsulfonylbutyl chloride (0.40 g) were added to a solution (15 ml) of 4-amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (0.52 g) in dimethylformamide, and the mixture was stirred at 70°-80° C. for 7.5 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with brine and dried. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. The obtained oil was treated with hydrochloric acid-ethanol and the obtained crystals were recrystallized from ethyl acetate to give 0.10 g of 4-amino-5-chloro-2-methoxy-N-((1-(4-phenylsulfonylbutyl)piperidin-4-yl)methyl)benzamide hydrochloride.
Reaction SMILES: [NH2:1][CH:2]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[CH:6][C:5]=2[CH:4]([Cl:16])[CH:3]1[OH:17]>FC(F)(F)C(O)=O>[ClH:16].[NH2:1][C@H:2]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[CH:6][C:5]=2[C@H:4]([Cl:16])[C@H:3]1[OH:17]
Reactant: NC1Cc2c(ccc3ccccc23)C(Cl)C1O
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: N[C@H]1Cc2c(ccc3ccccc23)[C@H](Cl)[C@H]1O
Yield: 67.7 %

Procedure:
3-Amino-1-chloro-1,2,3,4-tetrahydro-2-phenanthrenol (103 mg) in trifluoroacetic acid (10 ml) was refluxed for 3 hours. The green mixture was evaporated and the residue was taken up in methanol and acidified with a solution of hydrochloric acid in diethyl ether. The evaporation residue was treated with charcoal in methanol. Filtration gave a clear solution which was evaporated to yield the crude compound as a solid (99 mg). Recrystallization from ethanol/diethyl ether afforded the title compound (40 mg) as a white solid, m.p. 247° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:14])=[C:5]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]=1[CH3:21].Br[C:23]1[CH:32]=[CH:31][C:26]2[O:27][CH2:28][CH2:29][O:30][C:25]=2[CH:24]=1>>[O:27]1[C:26]2[CH:31]=[CH:32][C:23]([N:18]3[CH2:19][CH2:20][N:15]([C:5]4[C:4]([CH3:21])=[C:3]([O:2][CH3:1])[C:11]5[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=5[C:6]=4[CH3:14])[CH2:16][CH2:17]3)=[CH:24][C:25]=2[O:30][CH2:29][CH2:28]1
Reactant: COc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Reactant: Brc1ccc2c(c1)OCCO2
Product: COc1c(C)c(N2CCN(c3ccc4c(c3)OCCO4)CC2)c(C)c2c1OC(C)(C)C2
Yield: 22.5 %

Procedure:
By using 1-(7-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (436 mg, 1.50 mmol) synthesized in Reference example 96 and 6-bromo-2,3-dihydro-1,4-benzodioxine (484 mg, 2.25 mmol), the reaction was carried out in the same manner as Reference example 59 to synthesize the title compound 143 mg (yield 15%). Melting point was 167 to 168° C. (hexane).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([S:15]([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=1)(=[O:17])=[O:16])=[C:5]([C:12](O)=[O:13])[NH:6]2.Cl.[NH2:27][C@H:28]([C:31]([NH2:33])=[O:32])[CH2:29][OH:30].C(N(CC)CC)C.CN(C)C=[O:44]>O>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([S:15]([C:18]1[CH:19]=[C:20]([CH3:25])[CH:21]=[C:22]([CH3:24])[CH:23]=1)(=[O:17])=[O:16])=[CH:5][NH:6]2.[C:29]([C@@:28]([C:31]([NH2:33])=[O:32])([CH2:12][OH:13])[NH2:27])([OH:44])=[O:30]
Reactant: CN(C)C=O
Reactant: NC(=O)[C@@H](N)CO
Reactant: Cc1cc(C)cc(S(=O)(=O)c2c(C(=O)O)[nH]c3ccc(F)c(F)c23)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(C)cc(S(=O)(=O)c2c[nH]c3ccc(F)c(F)c23)c1
Product: NC(=O)[C@@](N)(CO)C(=O)O
Reaction time: 0.08 h
Yield: 97.9 %

Procedure:
4,5-Difluoro-3-(3,5-dimethylphenylsulphonyl)indole 2-carboxylic acid (3.52 g) and L-serinamide hydrochloride (2.77 g) were dissolved in anhydrous dimethylformamide (90 ml). Triethylamine (2.8 ml) was added and the mixture stirred for 5 min. Benzotriazol-1-yloxy-tris(dimethylamino)phosphosphonium hexafluorophosphate (BOP) (4.69 g) was added and the orange mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (350 ml) and the white solid precipitate collected by filtration, washed with water and dried to afford the title product (3.86 g) as a white powder (97.9% pure by hplc).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:6][C:7]1[CH:8]=[C:9]([C:13](Cl)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1.O>C(#N)C.CN(C)C=O>[Cl:6][C:7]1[CH:8]=[C:9]([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:10]=[CH:11][CH:12]=1
Reactant: c1c[nH]cn1
Reactant: Clc1cccc(C(Cl)(c2ccccc2)c2ccccc2)c1
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: Clc1cccc(C(c2ccccc2)(c2ccccc2)n2ccnc2)c1

Procedure:
27.2 g (0.4 mol) imidazole and 62.8 g (0.2 mol) of (m-chlorophenyl)-(diphenyl)-methyl chloride are heated to 80°C for 4 hours in 150 ml of dry acetonitrile and 50 ml dimethyl formamide. The solvent is then drawn off and the residue is digested with water to remove the imidazole hydrochloride. The residue is taken up in methylene chloride, dried over sodium sulfate, and the viscous oil remaining behind after the distilling off of the solvent is recrystallized from cyclohexane. 52 g (75% of the theory) of 1-[(m-chlorophenyl)-(bisphenyl)-methyl]-imidazole of m.p. 101°C are obtained.