Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:26])[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]4[CH2:24][CH2:23][CH2:22][N:21]([CH3:25])[CH2:20]4)=[CH:14][CH:13]=3)=[C:9]([C:27]3[CH:32]=[CH:31][C:30]([O:33]C)=[CH:29][CH:28]=3)[S:8][C:7]=2[CH:35]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:26])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH:19]4[CH2:24][CH2:23][CH2:22][N:21]([CH3:25])[CH2:20]4)=[CH:16][CH:17]=3)=[C:9]([C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[S:8][C:7]=2[CH:35]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OC3CCCN(C)C3)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Product: CN1CCCC(Oc2ccc(C(=O)c3c(-c4ccc(O)cc4)sc4cc(O)ccc34)cc2)C1
Yield: 72.2 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-[1-methylpiperidin-3-oxy]benzoyl)benzo[b]thiophene (310 mg, 0.636 mmol), ethane thiol (3.18 mmol), and aluminum chloride (508 mg, 3.81 mmol) were converted to 211 mg (72%) of the title compound by the procedure of Example 16. MS(FD) 460(M+). IR (CHCl3) ν max 3400, 3149, 2947, 1598, 1467, 1254, 1164.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.CC(C)([O-])C.[K+].[CH:19]([Cl:22])(Cl)[Cl:20]>CCCCC>[Cl:20][C:19]1([Cl:22])[C:2]([CH3:12])([CH3:1])[CH:3]1[C:4]1[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=1
Reactant: COc1ccc(C=C(C)C)cc1
Reactant: ClC(Cl)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCC
Product: COc1ccc(C2C(C)(C)C2(Cl)Cl)cc1

Procedure:
p-(2,2-Dichloro-3,3-dimethylcyclopropyl)anisole was prepared from 58.3 g. of p-(2,2-dimethylvinyl)anisole, 102 g. of potassium t-butoxide, 180 ml. of chloroform and 1800 ml. of pentane according to the procedure described above in Example 1, part (b). The product was recrystallized from hexane to produce p-(2,2-dichloro-3,3-dimethylcyclopropyl)anisole in the form of colorless needles, m.p. 54.5°-57°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].Cl[CH:17](OC1C=CC=CC=1)[C:18]#[N:19].CC([O-])(C)C.[K+].Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([C:12]([F:13])([F:14])[F:15])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[C:7]([CH2:17][C:18]#[N:19])[CH:8]=1
Reactant: N#CC(Cl)Oc1ccccc1
Reactant: COc1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(CC#N)c([N+](=O)[O-])cc1C(F)(F)F
Temperature: -10 °C
Yield: 77.7 %

Procedure:
A mixture of 1-Methoxy4-nitro-2-trifluoromethylbenzene (93 g, 0.421 mol) and 4 chlorophenoxyacetonitrile (77.55 g, 0.463 mol) in dry DMF (500 ml) was added dropwise over 0.75 h to a stirred solution of KOtBu (103.85 g, 0.927 mol) in dry DMF (400 ml) at −10° C. After complete addition the resulting purple solution was maintained at −10° C. for 1 h then poured into a mixture of ice/water (1.5 l) and 5 M aqueous HCl (1.5 l). The resulting mixture was extracted with dichloromethane (3×1 l). The combined extracts were washed with water (3 l), dried (Na2SO4) and evaporated under reduced pressure. The residue was chromatographed on silica using 10-40% ethyl acetate/petroleum ether as eluant to give the crude product which was recrystallised from ethyl acetate/petroleum ether to afford the title compound (85.13 g, 78%) as a white solid. Mp 103-104° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:40][CH2:41][CH2:42][CH2:43][O:44][C:45]1[CH:52]=[CH:51][CH:50]=[CH:49][C:46]=1[C:47]#[N:48]>>[C:47]([C:46]1[CH:49]=[CH:50][CH:51]=[CH:52][C:45]=1[O:44][CH2:43][CH2:42][CH2:41][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1)#[N:48]
Reactant: N#Cc1ccccc1OCCCCBr
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCOc4ccccc4C#N)cc3)cc21

Procedure:
Analogously to Method I, 0.160 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d) and 0.105 g of 2-(4-bromobutoxy)benzonitrile are reacted. The title compound is obtained as a colourless oil. Rf=0.18 (2:1 EtOAc-heptane); Rt=5.73.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH:6]([CH3:10])[C:7](Br)=[O:8].[CH3:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:14][C:13]1=[O:21]>C(=S)=S>[Br:5][CH:6]([CH3:10])[C:7]([C:18]1[CH:19]=[CH:20][C:15]2[S:14][C:13](=[O:21])[N:12]([CH3:11])[C:16]=2[CH:17]=1)=[O:8]
Reactant: CC(Br)C(=O)Br
Reactant: Cn1c(=O)sc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(Br)C(=O)c1ccc2sc(=O)n(C)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
A mixture of aluminum chloride (51.2 g) and 2-bromopropionyl bromide (25 g) in carbon disulfide (100 ml) was stirred at 35° C. to 40° C. for 30 minutes. To the mixture was added 3-methyl-2-benzothiazolinone (12.7 g) and the resulting mixture was stirred at 40° C. to 45° C. for 5 hours. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo to afford a crystalline residue. The residue was washed with diisopropyl ether to give 5-(2-bromopropionyl)-3-methyl-2-benzothiazolinone (17.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[C:4]([Br:11])[C:3]=1[OH:12].CC(C)([O-])C.[K+].[Cl:19][C:20]1[N:21]=[N:22][C:23](Cl)=[CH:24][C:25]=1[CH:26]([CH3:28])[CH3:27]>CN(C)C(=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[C:4]([Br:11])[C:3]=1[O:12][C:23]1[N:22]=[N:21][C:20]([Cl:19])=[C:25]([CH:26]([CH3:28])[CH3:27])[CH:24]=1
Reactant: CC(C)c1cc(Cl)nnc1Cl
Reactant: OCCc1cc(Br)c(O)c(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)c1cc(Oc2c(Br)cc(CCO)cc2Br)nnc1Cl
Temperature: 100 °C
Yield: 49.7 %

Procedure:
A mixture of 2,6-dibromo-4-(2-hydroxy-ethyl)-phenol (11) (183.3 g, 0.619 mol) in N,N-dimethyl acetamide (300 mL) was treated with potassium tert-butoxide (70.5 g, 0.59 mol) under nitrogen at room temperature. The suspension was heated to 100° C. and stirred until a solution formed. At this time, 3,6-dichloro-4-isopropyl pyridazine (7) (100 g, 0.50 mol) was added to the solution and the reaction mixture was stirred at 135° C. for 24 h. The reaction was cooled to room temperature, diluted with water (350 mL) and extracted with tert-butyl methyl ether (1×600 mL) followed by isopropyl acetate (1×600 mL). The organic layers were combined and washed with a 1N aqueous sodium hydroxide solution (1×256 mL) and water (2×200 mL). The organic layer was distilled to about 300 mL. The residue was treated with heptane (300 mL). The mixture was stirred under reflux for 30 min and then was cooled to room temperature. The resulting solid was filtered, washed with a 2:1 mixture of tert-butyl methyl ether: heptane (240 mL) and dried overnight to afford 2-[3,5-dibromo-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-ethanol (12) (112 g, 49%) as an off-white solid; LRMS for C15H15Br2ClN2O2 (M+) at m/z=450. Molecular Weight=450.5600; Exact Mass=447.9189
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[NH:23][C:22]2=[O:35])[CH2:17][CH2:16]1.[CH3:36][O:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Cl)=[CH:40][CH:39]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[N:23]([CH2:42][C:41]3[CH:44]=[CH:45][C:38]([O:37][CH3:36])=[CH:39][CH:40]=3)[C:22]2=[O:35])[CH2:17][CH2:16]1
Reactant: COc1ccc(CCl)cc1
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Product: COc1ccc(Cn2c(=O)n(C3CCN(c4ncnc5cc(OC)c(OC)cc45)CC3)c(=O)c3cc([N+](=O)[O-])ccc32)cc1
Yield: 62 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.63 mmol) of Compound 24 was used and 4-methoxybenzyl chloride was used in place of methyl iodide. As a result, 232.5 mg (yield: 62%) of Compound 12 was obtained as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:12]3[C:13]([CH3:36])=[C:14]([C:18]4[C:30]5[C:29]6[C:24](=[CH:25][C:26]([O:31]C)=[CH:27][CH:28]=6)[NH:23][C:22]=5[C:21]([C:33]([NH2:35])=[O:34])=[N:20][CH:19]=4)[CH:15]=[CH:16][CH:17]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1.BrB(Br)Br.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:12]3[C:13]([CH3:36])=[C:14]([C:18]4[C:30]5[C:29]6[C:24](=[CH:25][C:26]([OH:31])=[CH:27][CH:28]=6)[NH:23][C:22]=5[C:21]([C:33]([NH2:35])=[O:34])=[N:20][CH:19]=4)[CH:15]=[CH:16][CH:17]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(N4Cc5ccc(Cl)cc5C4=O)c3C)c12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(O)ccc4c23)cccc1N1Cc2ccc(Cl)cc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
To a heterogeneous mixture of 4-(3-(6-chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-methoxy-9H-pyrido[3,4-b]indole-1-carboxamide (prepared in the same manner as Example 15) (0.277 g, 0.557 mmol) in dichloromethane (20 mL) at 0° C. was added tribromoborane in dichloromethane (2.79 mL, 2.79 mmol) over 5 min. The heterogeneous mixture was stirred at room temperature for 3 hr and then poured into ice cold water (20 mL). The resulting mixture was basified with saturated NaHCO3 solution to pH 8 and extracted with ethyl acetate (3×40 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (0.217 g, 85% purity, 0.382 mmol, 68.5% yield) as a yellow solid. A pure sample was obtained through prep. reverse phase HPLC purification. LCMS (M+H)+=483.15. 1H NMR (500 MHz, DMSO-d6) δ: 11.61 (s, 1H), 9.89 (s, 1H), 8.34 (s, 1H), 8.20 (s, 1H), 7.88 (s, 1H), 7.81-7.77 (m, 3H), 7.72 (dd, J1=7.8 Hz, J2=1.2 Hz, 1H), 7.58 (m, 1H), 7.48 (dd, J1=7.5 Hz, J2=1.2 Hz, 1H), 7.23 (d, J=2.0 Hz, 1H), 7.12 (d, J=8.6 Hz, 1H), 6.60 (dd, J1=8.7 Hz, J2=2.3 Hz, 1H), 5.10 (d, J=17.6 Hz, 1H), 4.99 (d, J=17.6 Hz, 1H), 1.92 (s, 3H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10](Br)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].C(O[CH2:20][C:21]([F:37])=[CH:22][C:23]1([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)[CH2:25][CH2:24]1)(=O)C>O1CCCC1>[F:37][C:21]([CH2:20][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1)=[CH:22][C:23]1([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:34])([F:35])[F:36])=[CH:28][CH:27]=2)[CH2:25][CH2:24]1
Reactant: CC(=O)OCC(F)=CC1(c2ccc(OC(F)(F)F)cc2)CC1
Reactant: Brc1cccc(Oc2ccccc2)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: FC(=CC1(c2ccc(OC(F)(F)F)cc2)CC1)Cc1cccc(Oc2ccccc2)c1
Yield: 26.7 %

Procedure:
The method of Example 25 was repeated using a Grignard reagent, prepared from 3-phenoxyphenyl bromide (0.16 g), tetrahydrofuran (2 ml) and magnesium (17 mg) and 1-(3-acetoxy-2-fluoroprop-1-enyl)-1-(4-trifluoromethoxyphenyl)cyclopropane (Example 19) (0.128 g). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) and then preparative high performance liquid chromatography (column: C8; solvent: methanol; flow rate: 3 ml/min) to afford 1-(2-fluoro-3-(3-phenoxyphenyl)prop-1-enyl)-1-(4-trifluoromethoxyphenyl) cyclopropane (46 mg, 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][C@@H:13]([C:15]2[O:19][NH:18][C:17](=[O:20])[CH:16]=2)[CH2:12][CH2:11][N:10]1C(OC)=O.C(O)(=O)C>Br>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][C@@H:13]([C:15]2[O:19][NH:18][C:17](=[O:20])[CH:16]=2)[CH2:12][CH2:11][NH:10]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(F)cc1Cl
Agent: Br
Solvent: CC(=O)O
Product: O=c1cc([C@H]2CCN[C@@H](c3ccc(F)cc3Cl)C2)o[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
(2R,4S)-methyl 2-(2-chloro-4-fluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (382 mg, 1.08 mmol) was dissolved in hydrogen bromide (33% in acetic acid (8.5 mL, 48.46 mmol) and stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(2-chloro-4-fluorophenyl)piperidin-4-yl)isoxazol-3(2H)-one (304 mg, 95%). 1H NMR (600 MHz, dmso) δ 1.24 (q, 1H), 1.47 (dq, 1H), 1.85-1.91 (m, 1H), 1.97-2.02 (m, 1H), 2.75 (dt, 1H), 2.87 (tt, 1H), 3.09-3.14 (m, 1H), 3.97 (d, 1H), 5.73 (d, 1H), 7.19 (dt, 1H), 7.37 (dd, 1H), 7.66 (dd, 1H). HRMS Calculated for [C14H14ClFN2O2+H]+: 297.0806. Found: 297.0834
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]3[CH2:13][CH2:14][O:15][C:7]3([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[CH:23]=1.C[O-].[Na+].[CH3:27][O:28][CH2:29]Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:27][O:28][CH3:29])[C:10](=[O:12])[CH2:9][N:8]3[CH2:13][CH2:14][O:15][C:7]3([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[CH:23]=1
Reactant: O=C1CN2CCOC2(c2ccccc2Cl)c2cc(Cl)ccc2N1
Reactant: COCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCN1C(=O)CN2CCOC2(c2ccccc2Cl)c2cc(Cl)ccc21
Reaction time: 0.08 h

Procedure:
A solution of 2.8 g. of 10-chloro-11b-(2-chlorophenyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d] [1,4]benzodiazepin-6(7H)-one in 50 ml. of dimethylformamide was cooled to -10° and treated with 0.65 g. of sodium methoxide. After stirring for 5 minutes, the mixture was cooled to -40° and 1 ml. of chlorodimethyl ether was added. The cooling bath was removed and when the temperature had reached 0° the reaction mixture was poured into 300 ml. of ice-water. The precipitated material was collected by suction and dissolved in methylene chloride. The solution was dried over sodium sulfate, filtered and evaporated. The residue was crystallized from a mixture of ether and hexane to give, after recrystallization from ethanol, 10-chloro-11b-(2-chlorophenyl)-7-methoxymethyl-2,3,5,11b-tetrahydrooxazolo[3,2-d] [1,4] benzodiazepin-6(7H)-one as white prisms, m.p. 144°-147°.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.Br[C:26]1[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[C:14][C:26]4[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=4)=[C:8]3[N:7]=[C:6]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1cccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-cyclopropyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.7) (82 mg, 0.25 mmol) and commercially available 3-bromo-benzenesulfonamide (59 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (36 mg, 28%). MS (ISP) 483.5 [(M+H)+]; mp 262-264° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([OH:7])=O.C[Li].[CH3:14]COC(C)=O.Cl>CCOCC>[Br:11][C:9]1[CH:8]=[C:4]([C:5](=[O:7])[CH3:14])[CH:3]=[C:2]([Br:1])[CH:10]=1
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Li]C
Solvent: CCOCC
Product: CC(=O)c1cc(Br)cc(Br)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3,5-dibromobenzoic acid (2.5 g, 8.9 mmol) in Et2O (30 mL) at 0° C. was added methyllithium (1.6M in Et2O; 12.3 mL, 19.6 mmol) dropwise. The reaction was stirred at 0° C. for 2 hours, and then worked-up with EtOAc and 10% aqueous HCl. The crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: C(N[C:4]([NH:9][CH2:10][C:11]#C)=[N:5][CH2:6][CH2:7]S)#N.[C:13]([NH:15][C:16]([NH:21][CH2:22][CH2:23][C:24]#[CH:25])=[N:17][CH2:18][CH2:19][SH:20])#[N:14]>>[C:13]([NH:15][C:16]([NH:17][CH2:18][CH2:19][S:20][CH2:11][C:10]1[NH:9][CH:4]=[N:5][C:6]=1[CH3:7])=[N:21][CH2:22][CH2:23][C:24]#[CH:25])#[N:14]
Reactant: C#CCCNC(=NCCS)NC#N
Reactant: C#CCNC(=NCCS)NC#N
Product: C#CCCN=C(NC#N)NCCSCc1[nH]cnc1C

Procedure:
The general procedure of Example 1C is repeated except that the N-cyano-N'-propargyl-N"-(2-mercaptoethyl)guanidine utilized therein is replaced by an equimolar amount of N-cyano-N'-(3-butyn-1-yl)-N"-(2-mercaptoethyl)guanidine, and the title product is thereby produced.
Reaction SMILES: [Cl:1][C:2]([Cl:10])([F:9])[S:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.[O:11]1CCC[CH2:12]1.C=O>O.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]([Cl:10])([F:9])[S:3][C:4]1[CH:5]=[N:6][N:7]([CH2:12][OH:11])[CH:8]=1
Reactant: C1CCOC1
Reactant: FC(Cl)(Cl)Sc1cn[nH]c1
Agent: C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O
Product: OCn1cc(SC(F)(Cl)Cl)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.19 g of 4-{[dichlorofluoromethyl]thio}-1H-pyrazole was dissolved to 5 ml of tetrahydrofuran. 5 ml of formaldehyde 36% in water and 0.1 ml of tetrabutylammonium hydroxide 10% in water were added to the solution, followed by stirring at room temperature for 4 hours. Water was added to the reaction mixture, and extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.22 g of 4-{[dichlorofluoromethyl]thio}-1H-pyrazole-1-ylmethanol.
Reaction SMILES: [O:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([OH:21])=O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1)[CH3:2].Br.[OH:23][C:24]1[C:33]([OH:34])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[O:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][CH:32]=[C:33]([OH:34])[C:24]=4[OH:23])[CH2:29]3)=[O:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: COc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Reactant: Oc1ccc2c(c1O)CCNC2
Agent: Br
Product: COc1ccc(-c2nc(C(=O)N3CCc4c(ccc(O)c4O)C3)c3ccccc3n2)cc1
Yield: 9 %

Procedure:
Reaction of 2-(4-methoxylphenyl)quinazoline-4-carboxylic acid with 5,6-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide gave compound 23 (9% yield) as brown oil. 1H NMR (300 MHz, DMSO-d6) δ 2.62 and 2.88 (2t, 2H), 3.46 and 4.01 (2t, 2H), 3.87 (s, 3H), 4.33 and 4.87 (2s, 2H), 6.16 and 6.62 (2d, 1H), 6.51 and 6.72 (2d, 1H), 7.09-7.15 (m, 2H), 7.63-7.74 (m, 1H), 7.80-7.92 (2d, 1H), 8.02-8.12 (m, 2H), 8.44-8.51 (m, 2H); MS (ESI) m/z 428 ([M+H]+).
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].S(=O)(=O)(O)O>O>[O:13]=[C:11]1[C:6]2[CH:5]=[C:4]([C:1]([OH:3])=[O:2])[CH:19]=[CH:18][C:7]=2[O:8][C:9]2[C:10]1=[CH:14][CH:15]=[CH:16][CH:17]=2
Reactant: O=C(O)c1ccc(Oc2ccccc2C(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccc2oc3ccccc3c(=O)c2c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
A mixture of 29.9 g (0.11 mol) of 2-(4-carboxyphenoxy)benzoic acid (Example 10e) and 250 ml of concentrated sulfuric acid is heated at 80° C. for one hour. The resulting solution is then poured onto about 2.5 litres of water and the mixture is stirred vigorously for 30 minutes. The product which has precipitated is filtered off, washed with water and dried under a high vacuum. 23.15 g (85%) of 9-oxo-9H-xanthene-2-carboxylic acid, melting point>280° C., result as a beige. powder.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([S:12]([N:15]([CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:16][CH2:17][CH2:18][NH:19]C(OC(C)(C)C)=O)(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[ClH:36].CO>>[ClH:36].[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([S:12]([N:15]([CH2:27][CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:16][CH2:17][CH2:18][NH2:19])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)NCCCN(CCCc1ccccc1)S(=O)(=O)c1cccc2c(N)nccc12
Agent: Cl
Solvent: CO
Product: NCCCN(CCCc1ccccc1)S(=O)(=O)c1cccc2c(N)nccc12
Temperature: 25 °C

Procedure:
According to the method of Example 1, Step C, deprotection was performed (5° C., 2 hours) by using Intermediate 14 (125 mg) and 10% hydrogen chloride/methanol solution (2.5 ml). The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was added with methanol (0.5 ml) and diethyl ether (1.5 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (90 mg) as white powdery solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[NH:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)(O)[O-].[Na+].Br[CH2:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29]>C(O)(C)C>[OH:32][C:27]1([C:28]([F:31])([F:30])[F:29])[CH2:26][N:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=2)[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:13]1
Reactant: O=C(CBr)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccccc2)cc1
Yield: 58.9 %

Procedure:
To a mixture of N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Step 1) (16.5 g, 60.1 mmol) and sodium bicarbonate (10.1 g, 0.12 mol) in isopropanol (900 mL), 3-bromo-1,1,1-trifluoroacetone (8.7 ml, 84 mmol) was added. After heating the reaction mixture at 75–80° C. for 20 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by chromatography (silica gel, hexane/ethyl acetate, 45/55) to give 4-hydroxy-1-[4-(methylsulfonyl)phenyl]-2-phenyl-4-trifluoromethyl-4,5-dihydro-1H-imidazole (13.6 g, 59%) as awhite solid: mp 189–190° C. Anal. Calc'd for C17H15N2F3SO3: C, 53.12; H, 3.93; N, 7.29; S, 8.34. Found: C, 53.05; H, 3.90; N, 7.14; S, 8.38.
Reaction SMILES: [OH:1][C@:2]1([CH3:25])[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:23])[CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[Br:26]Br.O>CO>[Br:26][CH2:13][C:12](=[O:14])[C@@H:11]1[C@:15]2([CH3:24])[C@H:8]([C@H:7]3[C@H:18]([C:17](=[O:23])[CH2:16]2)[C@:19]2([CH3:22])[C@H:4]([CH2:3][C@@:2]([OH:1])([CH3:25])[CH2:21][CH2:20]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1
Reactant: BrBr
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@](C)(O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Solvent: O
Solvent: CO
Product: C[C@@]1(O)CC[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(=O)CBr)[C@@]4(C)CC(=O)[C@@H]32)C1

Procedure:
A stirred solution of 3α-hydroxy-3β-methyl-5α-pregnane-11,20-dione (5.0 g., 15.0 mmole) in methanol (300 ml.) was treated with a solution of bromine (1.0 ml.) in methanol (30 ml.) at 0° and at such a rate that the yellow colour of the solution disappeared before further addition of the bromine solution took place. The mixture was then poured into water, the precipitated title compound (2.8 g.) was collected by filtration and dried over P2O5 in vacuo.