Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:21]=1.[N:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]3[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][C:31]=3[N:32]=2)=[CH:24][CH:23]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH:15]1([N:7]2[CH2:8][CH:9]([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:37][C:34]4[CH:35]=[CH:36][C:30]5[O:29][C:28]([C:25]6[CH:24]=[CH:23][N:22]=[CH:27][CH:26]=6)=[N:32][C:31]=5[CH:33]=4)=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Nc1ccc2oc(-c3ccncc3)nc2c1
Reactant: CC1CN(C2CCCCC2)c2nc(Cl)ncc2N(C)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: CC1CN(C2CCCCC2)c2nc(Nc3ccc4oc(-c5ccncc5)nc4c3)ncc2N(C)C1=O

Procedure:
A solution of 0.05 g (0.00016 mole) of (rac)-2-chloro-9-cyclohexyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-19), 0.034 g, 0.00016 mole) of 2-pyridin-4-yl-benzooxazol-5-ylamine, 0.047 g, (0.00024 mole) of p-toluenesulfonic acid monohydrate and 4 mL of 2-propanol was heated at 180 degree for 2 hours in a microwave reactor. The reaction mixture was concentrated. The residue was diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (100:0-95:5) to give 0.047 g of (rac)-9-cyclohexyl-5,7-dimethyl-2-(2-pyridin-4-yl-benzooxazol-5-ylamino)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diaze-pin-6-one (I-26). HRMS (ES+) m/z Calcd for C27H29N7O2+H [(M+H)+]: 484.2456. Found: 484.2456.
Reaction SMILES: [CH3:1][Si:2]([CH3:30])([CH3:29])[O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH:19]([CH:20]=[CH:21][C:22](=[O:28])[CH2:23]CCCC)[CH2:18][CH2:17][C:12]21[O:16][CH2:15][CH2:14][O:13]2.C[Si](C)(C)OCCCCCCCC1C(C=CC(=O)[CH2:53][O:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)CCC21OCCO2.C[Si](C)(C)OCCCCCCCC1COC2(CCCC2)O1>>[OH:28][C:22]([CH3:23])([CH2:53][O:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[CH:21]=[CH:20][CH:19]1[CH2:18][CH2:17][C:12]2([O:13][CH2:14][CH2:15][O:16]2)[CH:11]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][O:3][Si:2]([CH3:30])([CH3:29])[CH3:1]
Reactant: CCCCCC(=O)C=CC1CCC2(OCCO2)C1CCCCCCCO[Si](C)(C)C
Reactant: C[Si](C)(C)OCCCCCCCC1C(C=CC(=O)COc2ccccc2)CCC12OCCO2
Agent: C[Si](C)(C)OCCCCCCCC1COC2(CCCC2)O1
Product: CC(O)(C=CC1CCC2(OCCO2)C1CCCCCCCO[Si](C)(C)C)COc1ccccc1

Procedure:
By proceeding in a similar manner to that hereinbefore described in Example 3(iii), but replacing the 6-(7-trimethylsiloxyheptyl)-7-(3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonane used as starting material by the appropriate quantity of 6-(7-trimethylsiloxyheptyl)-7-(3-oxo-4-phenoxybut-1-enyl)-1,4-dioxaspiro[4,4]nonane, there was prepared 7-(3-hydroxy-3-methyl-4-phenoxybut-1-enyl)-6-(7-trimethylsiloxyheptyl-1,4-dioxaspiro[4,4]nonane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:13]3[CH2:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[F:26][C:27]([F:32])([F:31])[C:28]([O-:30])=[O:29]>>[OH:30][C:28]([C:27]([F:32])([F:31])[F:26])=[O:29].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCCC(c2nc(-c3ccc(F)cc3)cs2)C1
Product: Fc1ccc(-c2csc(C3CCCNC3)n2)cc1
Product: O=C(O)C(F)(F)F

Procedure:
This compound was synthesized from tert-butyl 3-(4-(4-fluorophenyl)thiazol-2-yl)piperidine-1-carboxylate as described for example 46 step 4 (80 mg, crude) as a trifluoroacetate salt and it was carried through without further purification. MS (ESI) m/z: Calculated for C14H15FN2S: 262.09. found: 263.0 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=O.[C:24](OCC)(=[O:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C1CCN2C(=NCCC2)CC1.C(O)C>[CH3:23][O:22][C:17]1[CH:16]=[C:3]2[C:2](=[CH:19][C:18]=1[O:20][CH3:21])[NH:1][C:24](=[O:31])[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:4]2[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1c(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2[nH]c1=O
Temperature: 180 °C
Reaction time: 0.17 h
Yield: 92.1 %

Procedure:
A mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone (10.0 g), diethyl malonate (6.0 g) and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU)(0.396 g) was stirred at 180° C. for 10 minutes. After cooling, ethanol was added to the reaction mixture, and the crystals were collected by filtration to give ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2(1H)-quinolone-3-carboxylate (12.0 g, 91%) which was then recrystallized from chloroform-acetone. mp. 273°-276° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][N:10]([S:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)(=[O:19])=[O:18])[C:5]2=[CH:4][CH:3]=1
Reactant: Clc1ccc2[nH]ccc2n1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccccc1)n1ccc2nc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a suspension of 5-chloro-1H-pyrrolo[3,2-b]pyridine (5.0 g, 33 mmol, Adesis) in DCM (42 mL) was added benzenesulfonyl chloride (5.4 mL, 43 mmol, Aldrich), triethylamine (7.3 mL, 52 mmol) and 4-dimethylaminopyridine (0.40 g, 3.3 mmol). After stirring at room temperature for 1 hour, the mixture was diluted with EtOAc, washed with water (2×), brine, dried over sodium sulfate, filtered and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-20% EtOAc in hexanes to afford product as a white solid (8.7 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[CH:7][CH:6]=[CH:5]2.[Li][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[C:7]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:6]=[CH:5]2
Reactant: Cc1cc2ncccc2cc1Cl
Reactant: [Li]c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3ccccc3)ccc2cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Into a solution of 6-chloro-7-methylquinoline (1000 mg, 5.644 mmol) in THF (5 mL), which was cooled in ice/water bath under N2, was added PhLi (1.9 M in THF, 2.971 mL) dropwise over 5 min. After stirring at 0° C. for 15 min, the ice/water bath was removed and the reaction mixture was stirred at rt. After 4 h, MeOH (5 mL) was added to quench the reaction and the reaction mixture was stirred at rt overnight. After that time, the mixture was poured into water (20 mL) and extracted with EtOAc (3×30 mL). The organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in acetonitrile (30 mL) and DDQ (1282 mg) was added and the solution was stirred under N2 at rt for 24 h. After that time, the reaction mixture was poured into aqueous NaOH (3 N, 50 mL) and extracted with EtOAc (2×75 mL). The extracts were washed with aqueous NaOH (3N, 2×50 mL), water (2×50 mL) and brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford the title compounds; 1H NMR (CDCl3, 400 MHz) δ 2.60 (s, 3H), 7.47-7.55 (m, 3H), 7.83-7.86 (m, 2H), 8.04 (s, 1H), 8.10-8.16 (m, 3H); MS(ES): 254.1/256.1 (M/M+2).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][CH:17]=2)[CH:6]=[C:7](C2C=CC=CC=2)[CH:8]=1.C1C(=O)N([I:25])C(=O)C1.C(OCC)(=O)C.O>C(#N)C>[I:25][C:17]1[CH:16]=[N:15][N:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=12
Reactant: COc1cc(-c2ccccc2)cn2nccc12
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: COc1cccn2ncc(I)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
4-methoxy-6-phenylpyrazolo[1,5-a]pyridine (17, 200 mg, 0.892 mmol) and NIS (241 mg, 1.070 mmol) were dissolved in acetonitrile (20 mL) and stirred at room temperature for 1 hour. The reaction was then poured into ethyl acetate and water, extracted organics, washed 1N NaOH and brine, dried with magnesium sulfate, filtered, and concentrated to give a white solid. This was purified by column chromatography (0-30% ethyl acetate in hexanes, linear gradient) and to yield 3-iodo-4-methoxypyrazolo[1,5-a]pyridine (18, 310 mg, 0.885 mmol, 99% yield). MS APCI: [M+H]+ m/z 351.2.
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[CH3:11][C:12]1([CH3:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[CH2:13]1.[CH3:23]I>C1COCC1.O.CCO>[CH2:8]([O:7][C:3]([C:13]1([CH3:23])[C:14](=[O:21])[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]1([CH3:22])[CH3:11])=[O:10])[CH3:9]
Reactant: CC1(C)CC(=O)c2ccccc21
Reactant: CCOC(=O)OCC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C1(C)C(=O)c2ccccc2C1(C)C
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 52.8 %

Procedure:
To the suspension of NaH (3.05 g at 55% in mineral oil, 70 mmol, 1.4 equiv.) in THF (25 ml) was added neat diethyl carbonate (23.6 g, 200 mmol, 4 equiv.) followed by a solution of 3,3-dimethyl-1-indanone (8.0 g, 50 mmol, 1 equiv.) in THF (25 ml). The mixture was heated to 80° C. for 16 h, then cooled to 50° C. and treated with methyl iodide (21.3 g, 150 mmol, 3 equiv.). After 4.5 h further stirring at 50° C. the mixture was cooled to 5° C. and EtOH (20 ml) followed by H2O (20 ml) was introduced. After dilution with MTBE the phases were separated and the organic layer washed twice with brine, then dried over MgSO4. The residue obtained after concentration in a rotary evaporator was subjected to a short path distillation at 0.05 mbar and 90-115° C., followed by a fine distillation at 0.05 mbar, 112-116° C. to yield the product as a colourless oil (6.5 g, 53%).
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[S:15][C:14]([NH:16][C:17](=[O:40])[CH:18]([C:28]3[CH:33]=[CH:32][C:31]([S:34]([CH:37]4[CH2:39][CH2:38]4)(=[O:36])=[O:35])=[CH:30][CH:29]=3)[O:19][C:20]3[CH:25]=[CH:24]C(F)=[CH:22][C:21]=3F)=[N:13][CH:12]=2)=[CH:6][CH:5]=1.[Li+].[OH-:43]>C1COCC1.CO.O>[CH:37]1([S:34]([C:31]2[CH:32]=[CH:33][C:28]([CH:18]([O:19][CH:20]3[CH2:25][CH2:24][O:43][CH2:22][CH2:21]3)[C:17]([NH:16][C:14]3[S:15][C:11]([O:10][C:7]4[CH:6]=[CH:5][C:4]([C:3]([OH:2])=[O:41])=[CH:9][CH:8]=4)=[CH:12][N:13]=3)=[O:40])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH2:38][CH2:39]1
Reactant: COC(=O)c1ccc(Oc2cnc(NC(=O)C(Oc3ccc(F)cc3F)c3ccc(S(=O)(=O)C4CC4)cc3)s2)cc1
Reactant: [OH-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Oc2cnc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)cc1
Yield: 72.2 %

Procedure:
The compound of example B29 was obtained by similar method described in example B28 using 4-{2-[2-(4-Cyclopropanesulfonyl-phenyl)-2-(2,4-difluoro-phenoxy)-acetylamino]-thiazol-5-yloxy}-benzoic acid methyl ester (0.17 g, 0.29 mmol), LiOH (0.062 g, 1.48 mmol) in THF: MeOH: Water (1:1:1, 9 mL) to provide the title compound (0.117 g, 72%).
Reaction SMILES: [C:1]([O:18]CC)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:21][OH:22].[Na].OC1C=CC2C(=CC=CC=2)N=1>C(O)C>[C:1]([NH:21][OH:22])(=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: NO
Reactant: CCCCCCCCCCCCCCCC(=O)OCC
Agent: Oc1ccc2ccccc2n1
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCCCCCCCCC(=O)NO
Reaction time: 5 h
Yield: 85 %

Procedure:
14.2 g. of ethyl palmitate and 2 g. of hydroxylamine are reacted at room temperature in 300 ml. of ethanol in the presence of 1.7 g. of the sodium salt of 2-hydroxyquinoline. The reaction is complete in 5 hours, and 11.7 g, of palmitohydroxamic acid are obtained (yield: 85%), m.p. 100° - 101° C. after recrystallization from ethanol-petroleum ether(1:1).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH:16][NH2:17])[C:10]=2[F:18])[N:6]=1.[CH:19]1([CH2:24][C@H:25]([CH2:29][N:30]([CH:38]=[O:39])[O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[C:26](O)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH:16][NH:17][C:26](=[O:27])[C@H:25]([CH2:24][CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH2:29][N:30]([O:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[CH:38]=[O:39])[C:10]=2[F:18])[N:6]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Reactant: Cc1nc(NN)c(F)c(NCc2csc(N)n2)n1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1nc(NCc2csc(N)n2)c(F)c(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
6-{[(2-Amino-1,3-thiazol-4-yl)methyl]amino}-5-fluoro-4-hydrazino-2-methylpyrimidine (125 mg, 0.44 mmol), (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (130 mg, 0.44 mmol), and HOAt (65 mg, 0.48 mmol) were dissolved in 4 mL of DMF. NMM (0.15 mL, 1.32 mmol) was added, followed by EDC (96 mg, 0.48 mmol). After stirring overnight at room temperature, the reaction mixture was purified by RP-HPLC to provide [(2R)-3-[2-(6-{[(2-amino-1,3-thiazol-4-yl)methyl]amino}-5-fluoro-2-methyl-4-pyrimidinyl)hydrazino]-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (114 mg, 46%). LCMS: (M+H)+: 565.3.
Reaction SMILES: [I:1][C:2]1[C:7]([N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)=[CH:6][C:5]([NH2:13])=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1.CC1(C)[O:23][C:22]([C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[C:27]#[N:28])=[CH:21][C:20](=O)[O:19]1>>[C:27]([C:26]1[CH:25]=[C:24]([C:22](=[O:23])[CH2:21][C:20]([NH:13][C:5]2[CH:6]=[C:7]([N:8]3[CH:12]=[CH:11][CH:10]=[CH:9]3)[C:2]([I:1])=[CH:3][C:4]=2[N+:14]([O-:16])=[O:15])=[O:19])[CH:31]=[CH:30][CH:29]=1)#[N:28]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: Nc1cc(-n2cccc2)c(I)cc1[N+](=O)[O-]
Product: N#Cc1cccc(C(=O)CC(=O)Nc2cc(-n3cccc3)c(I)cc2[N+](=O)[O-])c1

Procedure:
The title compound was prepared from 4-iodo-2-nitro-5-pyrrol-1-yl-phenylamine (Example F2) (329 mg, 1.0 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example L1) (252 mg, 1.1 mmol) according to the general procedure M. Obtained as a yellow solid (436 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][O:6][S:5](=[O:8])[O:4][CH2:3]1.C(Cl)Cl.[O-:13][Mn](=O)(=O)=O.[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[CH3:1][C:2]1([CH3:9])[CH2:7][O:6][S:5](=[O:13])(=[O:8])[O:4][CH2:3]1
Reactant: CC1(C)COS(=O)OC1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC1(C)COS(=O)(=O)OC1
Yield: 129.2 %

Procedure:
10 g (0.067 mol) of 5,5-dimethyl-1,3,2-dioxathiane 2-oxide (prepared in accordance with Example 1), 70 ml of methylene chloride, 0.76 g (0.0033 mol) of benzyltriethylammonium chloride and 70 ml of water are placed in a 350 ml four-necked flask which is provided with a stirrer and a thermometer. 7.5 g (0.0475 mol) of KMnO4 are added portion-wise at 5°-10° C. and while stirring vigorously. After the addition the reaction mixture is stirred at room temperature for a further 30 minutes and suction filtered. The organic phase is separated. The residue is washed well on the suction filter with 20 ml of methylene chloride and the aqueous phase is again extracted with this new filtrate. The combined organic phases are extracted with 1 g of NaHSO3 in 20 ml of water and washed with a small amount of water. After drying over Na2SO4 and evaporation there are obtained 10.2 g of 5,5-dimethyl-1,3,2-dioxathiane 2,2-dioxide as a white powder with a m.p. of 80°-82° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].C=O.[CH3:14][NH:15][CH3:16].[CH:17](Cl)(Cl)Cl>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:14][N:15]([CH3:17])[CH3:16])#[N:2]
Reactant: ClC(Cl)Cl
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: CNC
Agent: C=O
Solvent: CCO
Product: CN(C)Cc1c[nH]c2ccc(C#N)cc12
Yield: 100 %

Procedure:
To a solution of 14.0 g (98.5 mmol, 1.0 equiv.) of 5-cyanoindole in 35 mL of ethanol was added 8.7 mL (108 mmol, 1.1 equiv.) of 40% aqueous formaldehyde and 12.2 mL (108 mmol, 1.1 equiv) of 40% aqueous dimethylamine. The flask was fitted with a reflux condenser topped with a cold finger condenser at -78° C. The solution was heated to reflux for eight hours at which time TLC indicated absence of starting material. The solution was poured into 350 mL of chloroform and washed once with 50 mL of 10% aqueous sodium carbonate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to yield 19.6 g (100%) of 5-cyano-3-(dimethylamino)methyl-1H-indole, pure by 1H NMR analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:9]=2)=[CH:4][CH:3]=1.N[C:32]1C=CC(C2C=C(C3C=CC=CC=3)N=C(OCCCCC(C)(C)C(OC)=O)C=2)=CC=1.CNC1C=CC(C2C=C(C3C=CC=CC=3)N=C(OCCCCC(C)(C)C(OC)=O)C=2)=CC=1>>[CH3:32][NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCCCOc1cc(-c2ccc(N)cc2)cc(-c2ccccc2)n1
Reactant: COC(=O)C(C)(C)CCCCOc1cc(-c2ccc(N)cc2)cc(-c2ccccc2)n1
Agent: CNc1ccc(-c2cc(OCCCCC(C)(C)C(=O)OC)nc(-c3ccccc3)c2)cc1
Product: CCOC(=O)CCCCCOc1cc(-c2ccc(NC)cc2)cc(-c2ccccc2)n1

Procedure:
When the procedure of Example 16 is followed and ethyl 6-{[4-(4-aminophenyl)-6-phenyl-2-pyridyl]oxy}hexanoate is replaced with methyl 6-{[4 -(4-aminophenyl)-6-phenyl-2-pyridyl]oxy}-2,2-dimethylhexanoate then the compound prepared is methyl 6-{[4-(4-methylaminophenyl)-6-phenyl-2-pyridyl]oxy}-2,2-dimethylhexanoate. (m.p.=77° C.)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].Br[C:12]1[CH:20]=[C:19]([F:21])[C:18]([Br:22])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15].C(OCC)(=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[Br:22][C:18]1[C:19]([F:21])=[CH:20][C:12]([O:10][C:3]2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1cc(Br)c(F)cc1Br
Reactant: COc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2cc(F)c(Br)cc2C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 2 L RB flask was charged with 2-fluoro-4-methoxyphenol (49.6 g, 349 mmol), 2,5-dibromo-4-fluorobenzoic acid (80 g, 269 mmol), ethyl acetate (1.316 mL, 13.43 mmol), cesium carbonate (192 g, 591 mmol) and toluene (1200 mL). To the mixture at was added copper(I) triflate toluene complex (2:1) (1.713 g, 8.06 mmol) and it was stirred at room temperature for 20 minutes. The solution was then heated to 75° C. for 16 hours at which point the toluene was removed under reduced pressure. The solution was dissolved in 1.5 liters of water and washed with 250 ml of EtOAc. The aqeuous layer was acidified to pH 1 with concentrated HCl and the resulting precipitant was collected by filtration and washed with water. The derived solid was washed with a 1:1 solution of ethyl acetate and hexane, then dried under vacuum to afford 5-bromo-4-fluoro-2-(2-fluoro-4-methoxyphenoxy)benzoic acid as a light brown solid. MS m/z=358.8 [M+H].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1Br.[CH2:9]([OH:14])[CH2:10][CH2:11][C:12]#[CH:13]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:14][CH2:9][CH2:10][CH2:11][C:12]#[C:13][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:13]#[C:12][CH2:11][CH2:10][CH2:9][OH:14]
Reactant: C#CCCCO
Reactant: Brc1ccccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: OCCCC#Cc1ccccc1C#CCCCO
Temperature: 85 °C
Reaction time: 144 h
Yield: 47.4 %

Procedure:
1,2-Dibromobenzene (10.94 g, 46.37 mmol), 4-pentyn-1-ol (9.36 g, 111.30 mmol), and bis(triphenylphosphine)palladium(II) dichloride (650 mg, 0.93 mmol) was stirred in triethylamine (150 mL) under nitrogen for 5 min. Copper(I) iodide (88 mg, 0.46 mmol) was added and the mixture was stirred for 4 hrs at 85° C. for 6 days. The mixture was cooled to room temperature and filtered through a celite pad, rinsed with ethylacetate. The combined filtrate was evaporated to dryness under reduced pressure. The resulting residue was purified by column chromatography (chloroform:methanol 30:1) to afford 5.33 g of the title compound. Yield: 47%. 1H NMR (300 MHz, D2O) δ 1.85 (m, 4H), 2.58 (t, J=6.6 Hz, 4H), 3.82 (t, J=6.0 Hz, 4H), 7.18 (m, 2H), 7.36 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 16.3, 31.4, 62.4, 80.2, 93.3, 126.0, 127.4, 131.8 ppm.
Reaction SMILES: Br.Br.[OH:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:6][C:5]=1[CH3:17].Cl[C:19]1[C:24]([CH3:25])=[C:23]([CH3:26])[N:22]=[C:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:3][C:4]1[C:5]([CH3:17])=[CH:6][C:7]([N:11]2[CH2:12][CH2:13][N:14]([C:19]3[C:24]([CH3:25])=[C:23]([CH3:26])[N:22]=[C:21]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:20]=3)[CH2:15][CH2:16]2)=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1nc(-c2ccccc2)nc(Cl)c1C
Reactant: Cc1cc(N2CCNCC2)cc(C)c1O
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(N2CCN(c3nc(-c4ccccc4)nc(C)c3C)CC2)cc(C)c1O
Temperature: 90 °C
Reaction time: 6 h
Yield: 75.9 %

Procedure:
A mixture of 4.42 g (12 mmol) of 1-(4-hydroxy-3,5-dimethylphenyl)piperazine dihydrobromide, 2.84 g (13 mmole) of 4-chloro-5,6-dimethyl-2-phenylpyrimidine, 1.66 g (12 mmol) of powdered K2CO3 and 38 ml of absolute DMF was warmed to 90° C., and 277 mg of powdered K2CO3 were added at 90° C. with stirring in each case after 10 minutes, after a further 25 minutes and after a further 60 minutes (in total 6 mmol of K2CO3), and the mixture was stirred for a further 6 hours at 95° C. The DMF was subsequently removed by distillation in vacuo, the residue was taken up in CH2Cl2 /water, the phases were separated after through mixing, and the aqueous phase was extracted a further three times with CH2Cl2. The combined CH2Cl2 extracts were dried, filtered and evaporated in vacuo. The crystalline residue (5.2 g) was boiled with 15 ml of methanol, and the crystals were filtered off under suction after cooling in an ice bath. In this fashion, 3.54 g (=76% yield) of pure 1-(4-hydroxy-3,5-dimethylphenyl)-4-(5,6-dimethyl-2-phenylpyrimidin-4-yl)piperazine, melting point 188°-89° C., were obtained;