Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:16][C:15]([C:17]4[C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[O:19][C:18]=4[CH2:26][CH2:27][CH2:28][CH3:29])=[N:14][CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:30].Br[CH2:32][C:33]#[N:34].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:16][C:15]([C:17]4[C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[O:19][C:18]=4[CH2:26][CH2:27][CH2:28][CH3:29])=[N:14][CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:30][CH2:32][C:33]#[N:34]
Reactant: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3c(Br)c(O)ccc3c2)o1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3c(Br)c(OCC#N)ccc3c2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
A mixture of 1-bromo-6-[2-(2-butyl-1-benzofuran-3-yl)-1,3-oxazol-5-yl]-2-naphthol (89 mg 0.192 mmol), prepared in the previous step, bromoacetonitrile (16 μL, 0.23 mmol) and cesium carbonate (127 mg, 0.389 mmol) in 20 mL of acetone was stirred under nitrogen at room temperature for 15 h (overnight). The acetone was removed under reduced pressure and the residue partitioned between methylene chloride and water. The organic layer was separated and the aqueous layer extracted two times with methylene chloride. The combined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to give ({1-bromo-6-[2-(2-butyl-1-benzofuran-3-yl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)acetonitrile (95 mg, 91%) as a brown solid, mp 144-146° C. Elemental Analysis for C27H21BrN2O3 Calc'd: C, 64.68; H, 4.22; N, 5.59. Found: C, 63.90; H, 4.10; N, 5.18.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:16])[O:6][CH2:7][C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:9]=1)([CH3:3])[CH3:2]>ClCCl.O=[Pt]=O>[CH:1]([C@@H:4]1[NH:9][C@H:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:7][O:6][C:5]1=[O:16])([CH3:3])[CH3:2]
Reactant: CC(C)C1=N[C@H](c2ccccc2)COC1=O
Agent: O=[Pt]=O
Solvent: ClCCl
Product: CC(C)[C@@H]1N[C@H](c2ccccc2)COC1=O
Reaction time: 5 h

Procedure:
To a solution of (5R)-3-isopropyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one (38) (1.03 g, 4.74 mmol, 1.0 equiv.) in anhydrous dichloromethane (50 mL) under an atmosphere of nitrogen was added PtO2 (103 mg, 0.1 equiv.). The mixture was consecutively degassed and purged three times with hydrogen and then stirred for 5 hours under an atmosphere of hydrogen. Filtration through a short pad of CELITE® diatomaceous earth and removal of solvent from the filtrate in vacuo yielded the crude product which was purified by flash column chromatography on silica eluting with petrol and diethyl ether (4:1) to furnish the title product as a waxy solid (662 mg, 64%); m.p. 61.5-62.5° C.; v(max)(KBr) 3326 (N—H—), 2960 (C—H), 1733 (C═O), cm−1; δH (250 MHz, CDCl3) 7.47-7.35 (5H, m, Ph); 4.33-4.18 (3H, m, PhCHCH2), 3.81 (1H, m, NHCH), 2.49, (1H, m, CH(CH3)2), 1.68 (1H, br, NH), 1.09 (3H, dd, J 6.75 Hz, CH(CH3)2×3), 1.05 (3H, dd, J 6.75, CH(CH3)2×3); δC, (62.5 MHz, CDCl3) 170.3, 138.5, 129.3, 129.1, 127.6, 74.9, 64.2, 57.3, 32.0, 19.4, 17.4; m/z (Cl, NH3), 237 (MNH4+, 5%), 220 (100%, MH+), 219 (22%), and 216 (6%); HRMS for C13H18NO2 requires 220.1333 found 220.1338. [α]D20 −92.1 (c 1.45 CHCl3).
Reaction SMILES: C(O[K])(C)(C)C.[Cl:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([F:15])[C:9]=1[OH:16].[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24](F)[CH:25]=1)[C:21]#[N:22].C1OCCOCCOCCOCCOCCOC1>CS(C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:16][C:9]2[C:10]([F:15])=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=2[Cl:7])[CH:25]=1)[C:21]#[N:22]
Reactant: Cc1ccc(F)c(O)c1Cl
Reactant: N#Cc1cc(F)cc(Cl)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)O[K]
Solvent: CS(C)=O
Product: Cc1ccc(F)c(Oc2cc(Cl)cc(C#N)c2)c1Cl
Yield: 79.4 %

Procedure:
The title compound was prepared as described herein using tBuOK (4.00 ml, 4.00 mmol), 2-chloro-6-fluoro-3-methylphenol (642 mg, 4.00 mmol), 3-chloro-5-fluorobenzonitrile (622 mg, 4.00 mmol) and 18-crown-6 (211 mg, 0.800 mmol) in dimethyl sulfoxide (16 ml) to give the title compound as a white solid (0.94 g, 79%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.33 (1H, s) 7.12-7.19 (2H, m) 7.07 (1H, t, J=8.9 Hz) 6.98 (1H, s) 2.40 (3H, s). LCMS: m/z 294 (M−1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.I[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:13]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=C1CCc2cc(O)ccc21
Reactant: CCCCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCOc1ccc2c(c1)CCC2=O
Reaction time: 3 h
Yield: 65 %

Procedure:
A solution of 5-hydroxy-1-indanone (1.00 g, 6.74 mmol), 1-iodooctane (1.34 mL, 7.42 mmol) and potassium carbonate (1.40 g, 10.12 mmol) were stirred together in acetonitrile at 80° C. After 3 h, the reaction was cooled, placed onto silica gel and eluted with 15% ethyl acetate/hexane to give 1.14 g of a white solid: 1H NMR (500 MHz, CDCl3): δ 7.67 (d, J=9.2 Hz, 1H), 6.88–6.90 (m, 2H), 4.03 (t, J=6.55 Hz, 2H), 3.08 (t, J=5.9 Hz, 2H), 2.67 (t, J=6.0 Hz, 2H), 1.80 (m, 2H), 1.42–1.50 (m, 2H), 1.24–1.38 (m, 8H), 0.89 (t, J=7.0 Hz, 3H); ESI-MS 261.1 (M+H).
Reaction SMILES: [C:1]1(=[O:8])O[C:5](=[O:6])[CH2:4][C:2]1=[CH2:3].[CH2:9]([NH2:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>N1C=CC=CC=1>[CH2:3]=[C:2]1[CH2:4][C:5](=[O:6])[N:18]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:1]1=[O:8]
Reactant: C=C1CC(=O)OC1=O
Reactant: CCCCCCCCCN
Solvent: c1ccncc1
Product: C=C1CC(=O)N(CCCCCCCCC)C1=O
Temperature: 90 °C

Procedure:
A solution of itaconic anhydride (0.1 M) in pyridine (20 ml)was treated with nonylamine (0.1 M). The reaction mixture was heated to 90° C. for six hours. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[C:4]([NH2:16])[C:5]([NH2:15])=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](O)=O>>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]2[NH:15][C:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)=[N:16][C:4]=2[C:3]=1[O:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cc(Oc2cccnc2)c(Cl)c(Oc2cccnc2)c1N
Reactant: O=C(O)c1ccccn1
Product: Clc1c(Oc2cccnc2)cc2[nH]c(-c3ccccn3)nc2c1Oc1cccnc1

Procedure:
In the same manner as in Example 68 but using 4-chloro-3,5-bis(pyridin-3-yloxy)-benzene-1,2-diamine and picolinic acid, the entitled compound was obtained as a pale yellow solid.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[C@H:22]2[C@H:26]([OH:27])[C@H:25]([OH:28])[C@@H:24]([CH2:29][O:30][CH3:31])[O:23]2)=[C:15]([NH:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:14]=1.C(N(CC)CC)C>O1CCCC1>[OH:27][C@@H:26]1[C@H:25]([OH:28])[C@@H:24]([CH2:29][O:30][CH3:31])[O:23][C@H:22]1[N:19]1[CH:18]=[N:17][C:16]2[C:20]1=[N:21][C:13]([CH2:12][NH:11][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])=[N:14][C:15]=2[NH:32][CH2:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCCc4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCCc4ccccc4)nc(CNS(=O)(=O)c4ccccc4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
Phenylsulfonylchloride (57 mg, 0.33 mmol) was added to a stirred solution of (2R,3R,4S,5R)-2-[2-(aminomethyl)-6-(phenethylamino)-9H-purin-9-yl]-5-(methoxymethyl)tetrahydro-3,4-furandiol (150 mg, 0.36 mmol) (preparation 48) and triethylamine (110 mg, 1.08 mmol) in tetrahydrofuran (24 ml). The reaction mixture was stirred for 30 min at room temperature and then the solvent was removed under reduced pressure. The residue was azeotroped with dichloromethane and then purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol (95:5) to give the title compound (180 mg) as a foam. MS: 577 (MNa+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([Mg]Br)C.[O:12]=[C:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].CO.C(Cl)Cl>C1COCC1>[OH:12][C:13]([C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(C)=O
Reactant: Ic1ccncc1
Agent: CC[Mg]Br
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)C(C)(O)c1ccncc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
4-Iodopyridine (15.0 g, 73 mmol) was taken up in dry THF (600 mL) and cooled to 0° C. and then ethylmagnesium bromide (3M solution in THF, 41.8 mL) was gradually added, maintaining the temperature at 0° C. over the period of 30 mins. To the above reaction mixture was then added a solution of ethyl 2-oxopropanoate (12.13 g, 104 mmol) in THF (100 mL). The reaction mixture was stirred at 0° C. for 1 hr. The reaction progress was monitored by TLC using solvent system MeOH:DCM (5:95). After completion of reaction, the reaction mixture was quenched with ice-cold water and extracted with EtOAc (3×1 Lit). The combined organic layers were dried over Na2SO4, and concentrated under vacuum. The crude product residue was combined with a batch of crude product obtained from a second reaction carried out at the same scale, and was purified by column chromatography using silica (100-200 mesh) and solvent system EtOAc:Hexane (4:6) to obtain 7 g (25%) of ethyl 2-hydroxy-2-(pyridin-4-yl)propanoate as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.52 (d, 2H, J=6 Hz), 7.44 (d, 2H, J=6 Hz), 6.2 (s, 1H), 4.08 (q, 2H, J=7.2 Hz), 1.60 (s, 1H), 1.12 (t, 3H, J=7.2 Hz); LC-MS m/z calculated for [M+H]+ 196.09. found 196.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][Cl:12])=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:13])[CH2:9][CH2:10][CH2:11][Cl:12])=[CH:6][CH:7]=1
Reactant: O=C(CCCCl)c1ccc(Br)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(CCCCl)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a solution of 1-(4-bromophenyl)-4-chlorobutan-1-one (1.00 g, 3.83 mmol) in methanol (20 mL) was added sodium borohydride (260 mg, 7.66 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour. 1 M HCl was added and the mixture was stirred for 15 minutes. Solvents were removed and the residue was extracted with ethyl acetate (10 mL×2). The combined organic layer were washed with brine, dried and concentrated to give target compound (1 g, 99%) as a light yellow oil.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH:39][C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)=[N:14][C:15]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:27][C:28]3[C:33]([F:34])=[CH:32][C:31]([O:35][CH2:36][CH3:37])=[CH:30][C:29]=3[F:38])[N:19]=2)=[N:16][CH:17]=1)(C(C)(C)C)(C)C.Cl.C(=O)([O-])O.[Na+]>O1CCOCC1>[CH2:36]([O:35][C:31]1[CH:30]=[C:29]([F:38])[C:28]([CH2:27][N:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]([C:15]3[N:14]=[C:13]([NH:39][C:40]4[CH:41]=[CH:42][N:43]=[CH:44][CH:45]=4)[C:12]([O:11][CH2:10][CH2:9][OH:8])=[CH:17][N:16]=3)=[N:19]2)=[C:33]([F:34])[CH:32]=1)[CH3:37]
Reactant: CCOc1cc(F)c(Cn2nc(-c3ncc(OCCO[Si](C)(C)C(C)(C)C)c(Nc4ccncc4)n3)c3ccccc32)c(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(OCCO)c(Nc4ccncc4)n3)c3ccccc32)c(F)c1
Reaction time: 0.5 h

Procedure:
224 mg of 5-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)-2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-N-(pyridin-4-yl)pyrimidin-4-amine (0.337 mmol, 1. eq.) were dissolved in 3 ml of dry dioxane under nitrogen atmosphere. 442 μl of 4 M hydrogen chloride solution in dioxane were added and gave immediately a suspension. This suspension was stirred for 30 minutes. Then 10 ml of a aq. saturated sodium hydrogen carbonate solution were added. The suspension was filtered off and washed with water to yield 210 mg (0.34 mmol, 97.0%) of the analytically pure target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.S(Cl)([Cl:14])(=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][C:8]=1[Cl:14]
Reactant: COc1cccc(OC)c1
Reactant: O=S(=O)(Cl)Cl
Product: COc1ccc(Cl)c(OC)c1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
Into a triple-necked flask of 500 cm3, provided with a magnetic stirring system, with a thermometer, with a calcium chloride trap and a dropping funnel, and cooled to 10° C., were introduced successively 97.5 (0.70 mole) of 1,3-dimethoxy benzene and then drop by drop 96.5 g (0.70 mole) of sulfuryl chloride. Once the addition was ended, the solution was brought back to ambient temperature and allowed to stand 2 h and then distilled.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]([C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[O:26])[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2c(C(=O)N3CCOCC3)cccc21
Product: CC1c2cccc(C(=O)N3CCOCC3)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with (1-Methyl-1,2,3,4-tetrahydro-isoquinolin-5-yl)-morpholin-4-yl-methanone to provide the title compound in moderate yield.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10](=[O:18])[NH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:35]=[C:36]=[O:37])(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([S:32]([NH:35][C:36]([N:9]2[C:10](=[O:18])[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]2[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:37])(=[O:33])=[O:34])=[CH:30][CH:31]=1
Reactant: O=C1NN(C(c2ccccc2)c2ccccc2)C1c1ccccc1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Product: O=C(NS(=O)(=O)c1ccc(Cl)cc1)N1C(=O)C(c2ccccc2)N1C(c1ccccc1)c1ccccc1
Yield: 53 %

Procedure:
Following the procedure of Example 2 and using 1-(diphenylmethyl)-4-phenyl-1,2-diazetidin-3-one (prepared according to Example 1C.) and p-chlorophenylsulfonylisocyanate there is obtained 890 mg (53%) of the title compound having a melting point of 162°-163° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH2:13])[CH2:7]1.[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:29](=[O:30])[CH2:28][C:25]2[CH:24]=[CH:23][C:22]([S:19]([CH3:18])(=[O:20])=[O:21])=[CH:27][CH:26]=2)[CH2:7]1
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Reactant: NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: CS(=O)(=O)c1ccc(CC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)cc1
Yield: 47.8 %

Procedure:
Example 39 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 9 (0.055 g) and 4-(methylsulphonyl)phenylacetic acid (0.050 g) to give the title compound (0.045 g).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([CH3:16])([CH3:15])[C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=1>C(Cl)(Cl)Cl>[Br:1][CH2:13][C:12](=[O:14])[C:11]([CH3:16])([CH3:15])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=1
Reactant: BrBr
Reactant: CC(=O)C(C)(C)Cc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(Cc1ccc(Cl)cc1)C(=O)CBr
Reaction time: 1 h
Yield: 97.3 %

Procedure:
98.8 g (0.62 mol) of bromine are added dropwise to 130 g (0.62 mol) of 1-(4-chlorophenyl)-2,2-dimethyl-3-butanone in 1000 ml of chloroform at room temperature. The reaction mixture is subsequently stirred for 1 hour and is then concentrated. 174.7 g (97.3% of theory) of 4-bromo-1-(4-chlorophenyl)-2,2-dimethyl-3-butanone of refractive index nD20 1.5570 are obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][NH:7]1.Cl[C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:28])[C:18]([C:25]([OH:27])=[O:26])=[CH:19][N:20]2[CH2:23][CH3:24])=[CH:15][C:14]=1[F:29]>N1C=CC=CC=1>[CH2:23]([N:20]1[C:21]2[C:16](=[CH:15][C:14]([F:29])=[C:13]([N:10]3[CH2:9][CH2:8][NH:7][CH:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[CH2:11]3)[CH:22]=2)[C:17](=[O:28])[C:18]([C:25]([OH:27])=[O:26])=[CH:19]1)[CH3:24]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: c1coc(C2CNCCN2)c1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4ccco4)C3)cc21
Yield: 44.6 %

Procedure:
A mixture of 2.508 g of 2-(2-furanyl)piperazine, 942 mg of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 10 ml of pyridine was refluxed for 24 hours, then the solvent was removed. The residue was triturated with ether and chloroform, the solid collected, dissolved in 40% acetic acid and adjusted to pH 7 with 1N sodium hydroxide. The resulting solid was collected, washed with methanol and ether and dried, giving 600 mg of the desired product, mp 198° C.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1.[CH:31]([C:33]1[CH:34]=[N:35][CH:36]=[C:37]([CH:40]=1)[C:38]#[N:39])=[CH2:32]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH:32]=[CH:31][C:33]2[CH:34]=[N:35][CH:36]=[C:37]([CH:40]=2)[C:38]#[N:39])=[CH:26][CH:25]=1
Reactant: C=Cc1cncc(C#N)c1
Reactant: Clc1ccc(I)cc1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: N#Cc1cncc(C=Cc2ccc(Cl)cc2)c1
Yield: 70 %

Procedure:
Prepare essentially as described in EXAMPLE 15 using palladium(II) acetate (0.002 g, 0.01 mmol), tri-o-tolylphosphine (0.06 g, 0.02 mmol), copper (I) iodide (0.001 g, 0.005 mmol), 1-chloro-4-iodobenzene (0.24 g, 1 mmol) and 5-vinylnicotinonitrile, (prepared essentially as described in PREPARATION 51), (0.195 g, 1.5 mmol) at 100° C. for 7 h to give the title compound (0.170 g, 70%).
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[C:14](Cl)(=[O:16])[CH3:15]>>[C:2]1([CH3:12])[CH:3]=[CH:4][C:5]([S:8]([O:11][C:14](=[O:16])[CH3:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Product: CC(=O)OS(=O)(=O)c1ccc(C)cc1
Temperature: 60 °C
Reaction time: 0.42 h

Procedure:
Acetyl chloride (100 ml.; density=1.104 g./ml.) was charged into a suitable reaction flask containing 30 g. (0.158 mole) p-toluenesulfonic acid monohydrate. Vigorous evolution of HCl gas occurred immediately. An efficient HCl trap was attached to the reaction system. The reaction mixture was then heated to mild reflux (~55° C.) and was held to this temperature for 25 minutes. Heating was stopped and the reaction mixture allowed to drop to room temperature over 10-20 minutes with stirring. Vacuum (~20-50 mm) was applied cautiously to remove acetyl chloride without carryover. At the same time the mixture was heated gradually to 60° C. Distillation of acetyl chloride was complete in ~30 minutes with collection in an ice cold flask for reuse. The oil obtained was then subjected to vacuum (~5-10 mm) to remove the last traces of acetyl chloride and acetic acid at 37° C. A snow white solid then crystallized in about 30 minutes as the title product.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[N:14]1([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)NN1CCN(C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NN1CCNCC1
Yield: 104.7 %

Procedure:
To a solution of N-(4-benzyloxycarbonyl-1-piperazinyl)-tert-butoxycarboxamide (28 g) in methanol (250 ml) was added 10% palladium on carbon (5 g), and the mixture was stirred at ambient temperature under 3 atm of hydrogen for 1 hour. Palladium on carbon was filtered off and the filtrate was concentrated to give N-(1-piperazinyl)-tert-butoxycarboxamide (17.6 g).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[S:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=2)=[CH:26]1>ClCCl>[S:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34]([N:9]3[CH2:10][C:11]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[NH:6][C:7]4[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=4)=[O:35])=[CH:32][CH:31]=2)=[CH:26]1
Reactant: c1ccc2c(c1)CNc1ccccc1N2
Reactant: O=C(Cl)c1ccc(-c2ccsc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc(-c2ccsc2)cc1)N1Cc2ccccc2Nc2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 2.0 g of 5,11-dihydro-10H-dibenz[b,e][1,4]diazepine and 7 ml of N,N-diisopropylethylamine in 30 ml of dichloromethane is added dropwise a solution of 3.15 g of 4-(3-thienyl)benzoyl chloride in 30 ml of dichloromethane. The mixture is stirred 16 hours at room temperature and diluted with dichloromethane (50 ml). The solution is washed with 30 ml each of H2O, 2N HCl, saturated NaHCO3, water and dried (Na2SO4). The solvent is removed under vacuum and the residue purified by chromatography on silica gel with hexane-ethyl acetate as eluent to give a solid.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[N:5]([C:8]1[CH:12]=[CH:11][S:10][C:9]=1[C:13](OC)=[O:14])=[C:6]=[S:7]>O1CCCC1>[CH2:1]([N:4]1[C:13](=[O:14])[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[NH:5][C:6]1=[S:7])[CH2:2][CH3:3]
Reactant: COC(=O)c1sccc1N=C=S
Reactant: CCCN
Solvent: C1CCOC1
Product: CCCn1c(=S)[nH]c2ccsc2c1=O
Reaction time: 16 h

Procedure:
In a sulfonation flask, 1.7 g (0.028 mol) of n-propylamine are added dropwise to 30 ml of tetrahydrofuran and 5.2 g (0.026 mol) of methyl 3-isothiocyanatothiophene-2-carboxylate, dissolved in 30 ml of tetrahydrofuran, such that the internal temperature does not rise above 35° C. The reaction mixture is then stirred for 16 hours at reflux temperature and the tetrahydrofuran is then removed in a water-jet vacuum. The residue is taken up in ethyl acetate and extracted three times with water. The organic phase is then dried over sodium sulfate and the solvent is removed in the water-jet vacuum, giving the 3-propyl-2-thioxo-2,3-di-hydro-1 H-thieno[3.2-d]pyrimidin-4-one crude product which can be purified by digestion in tert-butylmethyl ether. The slightly brownish powder (5.3 g) has a melting point of >230° C.