Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]([CH2:13][N:14]2[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]2=[O:24])[CH2:5][N:4]3[CH2:3][CH2:2]1.[I:25]I>C(Cl)(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[I:25][C:9]1[CH:8]=[C:7]2[C:12]3=[C:11]([O:1][CH2:2][CH2:3][N:4]3[CH2:5][CH:6]2[CH2:13][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH:10]=1
Reactant: II
Reactant: O=C1c2ccccc2C(=O)N1CC1CN2CCOc3cccc1c32
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1CC1CN2CCOc3cc(I)cc1c32
Reaction time: 68 h

Procedure:
To a suspension of (rac)-2-(2,3,5,6-tetrahydro[1,4]oxazino[2,3,4-hi]indol-6-ylmethyl)-1H-isoindole-1,3(2H)-dione (0.081 g, 0.253 mmol) and silver trifluoroacetate (0.059 g, 0.266 mmol) in CHCl3 (2.0 mL) was added a solution of iodine (0.067 g, 0.266 mmol) in CHCl3 (8.0 mL) dropwise at rt. The mixture was stirred for 68 h. Silver trifluoroacetate (0.03 g, 0.136 mmol) and solution of iodine (0.035 g, 0.136 mmol) in CHCl3 (6.0 mL) were added. The mixture was stirred at rt for 4 h and added again silver trifluoroacetate (0.02 g, 0.09 mmol) and solution of iodine (0.025 g, 0.10 mmol) in CHCl3 (5.0 mL). After stirring for another 2 h, the mixture was filtered through a pad of celite and washed with CHCl3. The filtrate was washed with Na2SO3 solution and dried (MgSO4). After filtration, the filtrate was concentrated in vacuo to dryness and the residue was subjected to prep TLC (EtOAc/hexane, 1:2) to give 0.046 g (41%) of light yellow oil as the title compound: 1H NMR (400 MHz, CDCl3) δ 7.81-7.78 (m, 2 H), 7.69-7.65 (m, 2 H), 6.98 (s, 1 H), 6.86 (s, 1 H), 4.34-4.29 (m, 2 H), 3.91-3.80 (m, 2 H), 3.62-3.58 (m, 1 H), 3.24-3.14 (m, 2 H), 3.04-3.00 (m, 1 H), 2.97-2.92 (m, 1 H); MS (EI) m/z 447 (M++H).
Reaction SMILES: CC(C)([O-])C.[K+].CN(C=O)C.[N+:12]([C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C@H:21]([CH2:24][OH:25])[O:20][C:19]=2[CH:26]=1)([O-:14])=[O:13].ClC1C=CC(O[CH2:33][C:34]#[N:35])=CC=1>CC(OC)(C)C>[OH:25][CH2:24][C@H:21]1[CH2:22][O:23][C:18]2[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[C:26]([CH2:33][C:34]#[N:35])[C:19]=2[O:20]1
Reactant: N#CCOc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc2c(c1)O[C@@H](CO)CO2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: N#CCc1c([N+](=O)[O-])ccc2c1O[C@@H](CO)CO2
Yield: 60 %

Procedure:
A 5 L 3-necked flask equipped with a mechanical stirrer is charged with solid potassium t-butoxide (103.00 g, 0.918 mol) and DMF (1900 mL). The stirred solution is cooled until the internal temperature is 0° C., and a DMF (1100 mL) solution containing [(2S)-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (47.33 g, 0.224 mol) and (4-chlorophenoxy)acetonitrile (39.05 g, 0.233 mol) is added over 45 min. The reaction is quenched with 1 N HCl (1 L) and the volatiles are removed by rotary evaporation (˜3 L removed). The residue is dissolved in water (2 L) and extracted with EtOAc (3×600 mL). The combined extracts are washed with water (2×300 mL), 1 N NaOH (3×400 mL) and brine (300 mL), and evaporated to give an orange/brown solid. The solid is suspended with stirring in MTBE (300 mL) for 30 min. The solid is collected by vacuum filtration, washed with MTBE (50 mL) and then suction dried giving the title compound (33.60 g, 60%) as a tan solid. LCMS (Standard Method): 2.14 min, 251 (M+H)+. 1H NMR (300 MHz, CDCl2) δ 7.77 (d, J=9.2 Hz, 1H), 7.00 (d, J=9.2 Hz, 1H), 4.48-4.37 (m, 2H). 4.28-3.91 (series of m, 5H), 2.32 (br s, 1H).
Reaction SMILES: C(O)(=O)C1C=CC=CC=1.[NH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[N:22]([CH2:23][C:24]3[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=3[C:26]#[N:27])[C:21](=[O:32])[N:20](C)[C:19](=[O:34])[CH:18]=2)[CH2:12]1.[ClH:35]>C1COCC1.O1CCOCC1>[NH2:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[N:22]([CH2:23][C:24]3[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=3[C:26]#[N:27])[C:21](=[O:32])[NH:20][C:19](=[O:34])[C:18]=2[Cl:35])[CH2:12]1
Reactant: Cl
Reactant: Cn1c(=O)cc(N2CCCC(N)C2)n(Cc2ccccc2C#N)c1=O
Agent: O=C(O)c1ccccc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)c(Cl)c(=O)[nH]c1=O

Procedure:
Compound 4 (100 mg) in THF (2 mL) was treated with 4M HCl in dioxane (1 mL) at rt for 1 h, concentrated, and then purified by LC-MS to give the title compound. 1H-NMR (400 MHz, DMSO-D6): δ ppm 12.0 (s, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.68 (t, J=7.7 Hz, 1H), 7.49 (t, J=7.7 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 5.09-5.21 (m, 2H), 3.17 (m, 2H), 2.96 (t, J=11.1 Hz, 1H), 2.86 (d, J=10.6 Hz, 1H), 2.65 (m, 1H), 1.90 (d, J=11.6 Hz, 1H), 1.57 (d, J=13.1 Hz, 1H), 1.19-1.31 (m, 1H), 1.03-1.15 (m, 1H). MS (ES) [m+H] calc'd for C17H19ClN5O2, 360.1; found, 360.1.
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([O:19][CH3:20])=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([CH3:21])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[F:23][C:24]1([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[CH2:27][NH:26][CH2:25]1.CC1NC(C2C=C(C=CC=2C)C(O)=O)=C(C)N=1.Cl.N1CC(C2C=CC(C#N)=CC=2)C1>>[CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([O:19][CH3:20])=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([N:26]3[CH2:25][C:24]([C:28]4[CH:29]=[CH:30][C:31]([C:32]#[N:33])=[CH:34][CH:35]=4)([F:23])[CH2:27]3)=[O:11])=[C:7]([CH3:21])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COc1nnc(-c2cc(C(=O)O)c(C)cc2C2CCC2)[nH]1
Reactant: N#Cc1ccc(C2(F)CNC2)cc1
Agent: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: Cl
Agent: N#Cc1ccc(C2CNC2)cc1
Product: COc1nnc(-c2cc(C(=O)N3CC(F)(c4ccc(C#N)cc4)C3)c(C)cc2C2CCC2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5, except 4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid (compound 89.9) and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4) were used in place of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7) and 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2), respectively. m/z (ES+) 446 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 13.64-13.05 (br, 1H), 7.96 (d, J=8.0 Hz, 2H), 7.76 (d, J=8.0 Hz, 2H), 7.56 (s, 1H), 7.41 (s, 1H), 4.61-4.38 (m, 4H), 4.19 (m, 1H), 3.92 (s, 3H), 2.42 (s, 3H), 2.16 (m, 1H), 2.02 (m, 1H), 1.89 (m, 1H), 1.75 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:21][C:22]#[N:23])[CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1.[Cl-].[NH4+].[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1)[CH2:21][C:22]1[NH:28][N:27]=[N:26][N:23]=1
Reactant: COc1ccc(Oc2c(Cl)cc(CC#N)cc2Cl)cc1C(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Oc2c(Cl)cc(Cc3nnn[nH]3)cc2Cl)cc1C(C)C
Yield: 33.4 %

Procedure:
To a stirred solution of 3,5-dichloro-4-(4-methoxy-3-isopropylphenoxy)-phenylacetonitrile (160 mg) in 3.0 ml of dimethyl formamide, ammonium chloride (500 mg) and sodium azide (600 mg) was added at reflux. After 2 hours the reaction-mixture was concentrated, treated with 6 M hydrochloric acid and extracted several times with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered and concentrated. The residue was purified by column chromatography (silica gel, 96:4:1 chloroform/methanol/acetic acid) to give 60 mg (34%) of 3,5-dichloro-4-(4-methoxy-3-isopropylphenoxy)benzyltetrazole.
Reaction SMILES: Cl[C:2]1[C:3]([C:18]#[N:19])=[N:4][CH:5]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=2[CH3:17])[CH:7]=1.[CH3:20][C:21]1[CH:22]=[CH:23][C:24](B2OC(C)(C)C(C)(C)O2)=[C:25]([NH:27]C(=O)OC(C)(C)C)[CH:26]=1>>[CH3:17][C:11]1[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:10]=1[C:9]#[C:8][C:6]1[CH:5]=[N:4][C:3]2[C:2]([CH:7]=1)=[C:24]1[CH:23]=[CH:22][C:21]([CH3:20])=[CH:26][C:25]1=[N:27][C:18]=2[NH2:19]
Reactant: Cc1ccc(C#Cc2cnc(C#N)c(Cl)c2)c(C)c1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(NC(=O)OC(C)(C)C)c1
Product: Cc1ccc(C#Cc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1

Procedure:
2-((2,4-Dimethylphenyl)ethynyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine was prepared from 3-chloro-5-((2,4-dimethylphenyl)ethynyl)picolinonitrile (from Example 47/Step 3) and tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (from Example 5/Step 2) following the procedures described for Example 44, step 4.
Reaction SMILES: C(O[C:4](=[O:19])[C:5]([N:10]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[CH:11]1)=[CH:6][N:7](C)C)C.[NH:20]([C:22]1[N:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=1)N.C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[OH:29][CH2:28][C:25]1[CH:24]=[CH:23][C:22]([N:20]2[C:4](=[O:19])[C:5]([N:10]3[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[N:12]=[CH:11]3)=[CH:6][NH:7]2)=[N:27][CH:26]=1
Reactant: CCOC(=O)C(=CN(C)C)n1cnc(C(F)(F)F)c1
Reactant: NNc1ccc(CO)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=c1c(-n2cnc(C(F)(F)F)c2)c[nH]n1-c1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.0 g (3.6 mmol) of the compound from Example 44A and 502 mg (3.6 mmol) of the compound from Example 4A are dissolved in 1 ml glacial acetic acid and the mixture is stirred at RT for 16 h. Thereafter, 200 mg (1.4 mmol) of the compound from Example 4A are again added and the mixture is stirred at RT for a further 20 h. The reaction mixture is taken up in 5 ml ethyl acetate and the mixture is adjusted to pH 7 with dilute aqueous sodium bicarbonate solution. The aqueous phase is concentrated in vacuo, 1.5 ml (4.0 mmol) 21% strength ethanolic sodium ethylate solution are added to the residue and the mixture is stirred at RT for 4 h. The precipitate is filtered off and washed with ethanol.
Reaction SMILES: [NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl>[NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:35](=[O:42])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCN)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCNC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
4-Amino-N-(1-(6-aminohexyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (1.00 g) was dissolved in dichloromethane (25 ml). Triethylamine (0.42 ml) was added, and a solution of benzoyl chloride (0.32 ml) in methylene chloride was dropwise added under ice-cooling. The mixture was stirred at room temperature for 14 hr, and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 0.35 g of 4-amino-N-(1-(6-benzoylaminohexyl)-piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][NH2:5].[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=S.CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][NH:5][C:12]1[S:11][CH2:17][C:15](=[O:16])[N:14]=1
Reactant: O=C1CSC(=S)N1
Reactant: Cc1cccc(Cl)c1CN
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(Cl)c1CNC1=NC(=O)CS1
Temperature: 0 °C
Reaction time: 72 h
Yield: 28.5 %

Procedure:
To a solution of 2-chloro-6-methylbenzylamine (650 mg, 4.2 mmol) and Rhodanine (559 mg, 4.2 mmol) in acetonitrile (25 mL) was added DIPEA (1.74 mL, 10 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (1.22 g, 4.5 mmol) was added in one portion. After addition, the suspension was allowed to warm to room temperature and stirred for 3 days. The resulting black solids were filtered through a plug of celite and washed with dichloromethane (500 mL) and methanol (250 mL). The combined solvents were removed under the vacuum and the crude residue was dissolved in ethyl acetate (25 mL) at hot condition and stored in the refrigerator overnight. Then, the solids were collected by filtration and washed with ethyl acetate. After drying in air, 305 mg (28.5% yield) of 2-(2-chloro-6-methylbenzylamino)-thiazol-4-one was isolated as a white amorphous solid: EI-HRMS m/e calcd for C11H11ClN2OS (M+) 254.0281. found 254.0282.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:9][CH2:10]CCN)[CH:5]=[CH:6][C:7]=1Cl.FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)C=O.[C:30]([NH:33][C:34]1([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH2:39][CH2:38][N:37]([CH:40]([CH2:53][C:54]2[CH:59]=[C:58]([C:60]([F:63])([F:62])[F:61])[CH:57]=[C:56]([C:64]([F:67])([F:66])[F:65])[CH:55]=2)[CH2:41][CH:42]([C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=2)[CH2:43][NH2:44])[CH2:36][CH2:35]1)(=[O:32])[CH3:31].C1(CC=O)C=CC=CC=1>CO.ClCCl>[C:30]([NH:33][C:34]1([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH2:35][CH2:36][N:37]([CH:40]([CH2:53][C:54]2[CH:55]=[C:56]([C:64]([F:65])([F:66])[F:67])[CH:57]=[C:58]([C:60]([F:62])([F:61])[F:63])[CH:59]=2)[CH2:41][CH:42]([C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=2)[CH2:43][NH:44][CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=2)[CH2:38][CH2:39]1)(=[O:32])[CH3:31]
Reactant: CC(=O)NC1(c2ccccc2)CCN(C(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC(CN)c2ccc(Cl)c(Cl)c2)CC1
Reactant: NCCCCc1ccc(Cl)c(Cl)c1
Agent: O=CCc1ccccc1
Agent: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CO
Solvent: ClCCl
Product: CC(=O)NC1(c2ccccc2)CCN(C(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC(CNCCc2ccccc2)c2ccc(Cl)c(Cl)c2)CC1

Procedure:
Using a procedure similar to that described in Example 1, except replacing the (3,4-dichlorophenyl)butylamine and the 3,5-bis(trifluoromethyl)benzaldehyde used therein with 4-(4-acetamido-4-phenylpiperidino)-2-(3,4-dichlorophenyl)-N-[3,5-bis(trifluoromethyl)benzyl]butylamine and phenylacetaldehyde, respectively, the title compound was prepared; mp 55-57° C.; partial NMR (DMSO): 7.1-6.95 (broad m,11), 3.88 (d,1), 3.65 (d,1), 3.35(d,1), 3.15(d,1), 1.85 (s,3); MS: m/z=764(M+1,100%); TLC: Rf=0.44 (10:1 dichloromethane:methanol). Analysis for C40H41Cl2F6N3O: Calculated: C, 62.83; H, 5.40; N, 5.50; Found: C, 63.18; H, 5.71; N, 5.35.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[N:13]=[CH:14][S:15][CH:16]=2)=[O:9])[CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][C:37]=1O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O>[CH:44]1[C:45]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:41]=[CH:42][C:43]=1[O:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[N:13]=[CH:14][S:15][CH:16]=2)=[O:9])[CH2:4]1
Reactant: O=C(OCc1cscn1)N1CCC(CO)C1
Reactant: Oc1ccc2ccccc2c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(OCc1cscn1)N1CCC(COc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 39.5 %

Procedure:
0.25 g (1.03 mmol) of thiazol-4-ylmethyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate is dissolved in 8 ml of toluene. 0.35 g (1.34 mmol) of triphenylphosphine and 0.16 g (1.13 mmol) of naphth-2-ol are added and then the medium is cooled to 0° C. for slow addition of a solution of 0.27 g (1.34 mmol) of diisopropyl azodicarboxylate in 2 ml of toluene. The medium is stirred at ambient temperature for 14 hours. The residue obtained is taken up in water and extracted twice with dichloromethane. The combined organic phases are washed with a saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated under vacuum. The residue is purified by chromatography on silica gel, elution being carried out with a 99/1 to 98/2 mixture of dichloromethane and methanol. 0.15 g of the expected product is obtained in the form of a powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14](=[O:15])[CH2:13][C:12](C)(C)[CH2:11][C:10]1=[O:18].[C:19](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:19][O:18][C:10]1[CH2:11][CH2:12][CH2:13][C:14](=[O:15])[C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(C2C(=O)CC(C)(C)CC2=O)c(C)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC1=C(c2ccc(C)cc2C)C(=O)CCC1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
A solution of 10.00 g (0.0409 mol) of 2-(2',4'-dimethylphenyl)-5,5-dimethyl-1,3-cyclohexanedione, 21.42 g (0.155 mol) of anhydrous potassium carbonate, 17.59 g (0.124 mol) iodomethane, and 500 ml of anhydrous acetone was refluxed overnight. The reaction mixture was then cooled to room temperature, filtered, and the acetone removed. The residual solid was taken up in 250 ml of CH2Cl2, washed with water, 0.25 N NaOH, 1 N HCl, and water again. The solution was dried (MgSO4) and the solvent removed. The resulting solid was recrystallized from isopropyl ether to give 7.60 g (72% yield) of a white crystalline solid, m.p. 122°-23° C. The compound prepared by the above synthesis has the following structure: ##STR27##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>C(Cl)Cl>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]3)=[O:9])=[CH:6][CH:7]=2)=[O:26])=[CH:20][CH:19]=1
Reactant: CN1CCN(C(=O)c2ccc(N)cc2)CC1
Reactant: O=C=Nc1ccc(Br)cc1
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc(NC(=O)Nc3ccc(Br)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.8 %

Procedure:
To a solution of (4-amino-phenyl)-(4-methyl-piperazine-1-yl)-methanone (10.0 g, 0.0456 mol) and TEA (4.7 g, 0.0456 mol) in DCM (150 mL) was added 4-bromophenyl isocyanate (10.9 g, 0.0547 mol). The reaction mixture was stirred at room temperature for 12 h. The white solid was obtained and was filtered and dried to afford the title compound [15.0 g, 79%]; LC-MS (ESI): Calculated mass: 416.1; Observed mass: 417.1 [M+H]+ (RT: 0.23 min).
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.C(N(CC)CC)C.[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>C(Cl)(Cl)Cl>[S:17]([O:3][CH2:4][C@@H:5]([OH:6])[CH2:7][OH:8])([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)OC[C@@H](CO)O1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)CO)cc1
Yield: 67.8 %

Procedure:
8.6 g of (R)-glycerol acetonide [bp.: 88°-106° C. (18 mmHg); specific rotation: [α]D25 -12.10° (c 5.64, methanol)] was dissolved in 70 ml of chloroform, and 10.0 g of triethylamine was added. With stirring and ice cooling, a solution of 13.8 g of tosyl chloride in 30 ml of chloroform was added dropwise, and the mixture was stirred overnight. The reaction mixture was washed with an aqueous solution of potassium hydrogen carbonate and water, and the solvent was evaporated. The residue (18.7 g) was dissolved in 75 ml of acetone, and 225 ml of 1N hydrochloric acid was added. The mixture was stirred at 80° C. for 30 minutes. The reaction mixture was concentrated and extracted with 450 ml of ethyl acetate. The extract was washed with water, and the solvent was evaporated. The residue was purified by silica gel column chromatography [solvent: chloroform-methanol (40:1)] to give 10.86 g (yield 67.8%) of (S)-3-tosyloxy-1,2-propanediol as colorless needles having a melting point of 57° to 60° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.[OH:18]O>CO>[Br:1][C:2]1[N:3]=[CH:4][C:5]([OH:18])=[CH:6][C:7]=1[Cl:8]
Reactant: CC1(C)OB(c2cnc(Br)c(Cl)c2)OC1(C)C
Reactant: OO
Solvent: CO
Product: Oc1cnc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.6 %

Procedure:
To crude 2-bromo-3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Preparation 238, 8.27 g, 26.0 mmol) was added methanol (100 mL), and the stirred solution cooled in an ice bath. To the solution was added hydrogen peroxide solution (35% in water, 4.25 mL, 43.8 mmol) over 5 minutes. The solution was allowed to warm slowly to room temperature for 18 hours. The reaction was quenched by addition of 1M aqueous sodium thiosulfate solution (500 mL), with rapid stirring for 15 minutes. The organics were removed in vacuo, and brine (100 mL) was added. The aqueous phase was extracted into ethyl acetate (3×100 mL). The combined organic phases were dried over magnesium sulfate, filtered and the solvent removed to leave an off white solid. The solid was triturated in 4:1 heptene:ethyl acetate and filtered to afford the title compound as a white solid (2.20 g, 41%).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH:3]=[CH2:4].[Br:7][C:8]1[CH:16]=[C:15]([Br:17])[CH:14]=[C:10]([C:11]([OH:13])=O)[C:9]=1[OH:18].N1C(C)=CC=CC=1C>CC(C)=O>[C:1]([O:13][CH2:11][C:10]1[C:9](=[C:8]([Br:7])[CH:16]=[C:15]([Br:17])[CH:14]=1)[OH:18])(=[O:5])[CH2:2][CH:3]=[CH2:4]
Reactant: O=C(O)c1cc(Br)cc(Br)c1O
Reactant: C=CCC(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: CC(C)=O
Product: C=CCC(=O)OCc1cc(Br)cc(Br)c1O

Procedure:
3,5-Dibromosalicyl 3-butenoate is prepared by reaction of an acetone solution of 3-butenoyl chloride and 3,5-dibromosalicylic acid in the presence of 2,6-lutidine. The 3-butenoate ester is isolated and purified. In a second step, the desired oxirane, 3,5-dibromosalicyl 3,4-oxabutanoate, is prepared by reaction of 3,5-dibromosalicyl 3-butenoate and 3-chloroperbenzoic acid in chloroform solution. The desired oxirane is isolated and purified.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]([C:7]1[NH:8][CH:9]=[C:10]([S:12][C:13]#N)[CH:11]=1)=[O:6].BrC[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.CC(O)(C)C>[CH2:13]([S:12][C:10]1[CH:11]=[C:7]([C:5]([O:4][CH3:3])=[O:6])[NH:8][CH:9]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCCc1ccccc1
Reactant: COC(=O)c1cc(SC#N)c[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: COC(=O)c1cc(SCCc2ccccc2)c[nH]1
Temperature: 60 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
A solution of sodium hydroxide (88.0 mg, 2.20 mmol) in degassed H2O (0.500 mL) was added to a mixture of 2-methoxycarbonyl-4-thiocyanopyrrole (0.200 g, 1.10 mmol), prepared according to the procedure described in J. Chem. Soc. Perkin Trans. 2 1990, 699, and (2-bromoethyl)benzene (0.165 mL, 1.21 mmol) in degassed t-BuOH (2.0 mL). The reaction mixture was stirred at 60° C. for 2 h, cooled to rt and concentrated. The residue was dissolved in CH2Cl2 (50 mL) washed with H2O (2×25 mL), dried over anhydrous Na2SO4, concentrated and purified by chromatography on silica gel with MeOH and CH2Cl2 (0-10% gradient) as the mobile phases to afford 0.247 g of the title compound as a light yellow oil: 1H NMR (500 MHz, CDCl3) δ 2.83-2.88 (m, 2H), 2.89-2.95 (m, 2H), 3.87 (s, 3H), 6.94-6.97 (m, 1H), 7.00 (dd, J=2.7, 1.6 Hz, 1H), 7.14-7.22 (m, 3H), 7.26-7.30 (m, 2H), 9.30 (br. s., 1H); HPLC a) column: Phenomenex Luna 5μ 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% H3PO4 to 90% MeOH/10% H2O/0.1% H3PO4; 1 min hold, 4 mL/min UV detection at 220 nm, 3.561 min retention time, (>95%); HPLC b) column: Phenomenex Luna C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold; 4 mL/min, UV detection at 220 nm, 3.535 min retention time; MS (ES) 262 [M+H]+.