Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21](O)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:47][CH:48]1[CH2:53][CH2:52][CH2:51][NH:50][CH2:49]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:47][CH:48]1[CH2:53][CH2:52][CH2:51][N:50]([C:21]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:10]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][CH2:6]2)=[O:11])=[CH:20][CH:19]=3)=[O:22])[CH2:49]1
Reactant: FC1CCCNC1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCCC(F)C4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 3-fluoropiperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12]CC)=O)=[C:8](F)[CH:7]=1.O.[OH-].[Li+].[SH:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C.O>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]2[C:10]([OH:12])=[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[S:26][C:8]=2[CH:7]=1
Reactant: CCOC(=O)CS
Reactant: CCOC(=O)c1ccc(OCc2ccc(Cl)cc2Cl)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2cc(OCc3ccc(Cl)cc3Cl)ccc2c1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of ethyl 4-((2,4-dichlorobenzyl)oxy)-2-fluorobenzoate (2.0 g) in DMF (dry) (40 mL) were added lithium hydroxide monohydrate (0.978 g) and ethyl 2-mercaptoacetate (1.92 mL) at room temperature. The mixture was stirred at room temperature for 2 d. The mixture was diluted with water and the precipitate was collected by filtration, and washed with IPE to give the title compound (2.30 g).
Reaction SMILES: C(=O)([O-])O.[Na+].[C:6]([OH:10])(=[O:9])[CH2:7][OH:8].CN(C)C=O.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>O>[C:6]([O:10][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)(=[O:9])[CH2:7][OH:8]
Reactant: COc1ccc(CCl)cc1
Reactant: O=C(O)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COC(=O)CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
Sodium hydrogen carbonate (2.20 g, 26.3 mg) was added to a solution of glycolic acid (2.00 g, 26.3 mmol) in water (2.00 mL), and the mixture was stirred for one hour at room temperature. The solvent was distilled off from the reaction mixture under reduced pressure, and to a dimethylformamide (10.0 mL) solution of the resulting residue, p-methoxybenzyl chloride (4.10 g, 26.3 mmol) was added. The mixture was stirred for 2 hours at room temperature. Water was added to the reaction mixture, and the mixture was subjected to extraction with ethyl acetate. The organic layer thus obtained was washed sequentially with water and saturated brine, and was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Thus, a crude product of the title compound (4.24 g) was obtained.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]#[CH:10])(=O)=O.[N:11]1([C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH2:6]([N:14]1[CH2:15][CH2:16][N:11]([C:17]2[N:18]=[CH:19][CH:20]=[CH:21][N:22]=2)[CH2:12][CH2:13]1)[CH2:7][CH2:8][C:9]#[CH:10]
Reactant: C#CCCCOS(C)(=O)=O
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C#CCCCN1CCN(c2ncccn2)CC1
Yield: 66.4 %

Procedure:
A solution of pent-4-ynyl methanesulfonate (1.05 g), 2-(piperazin-1-yl)pyrimidine (1.02 g) and diisoproylethylamine (1.2 mL) in THF (5 mL) was heated to reflux overnight. The mixture was concentrated, diluted with aq. NaOH 2M (10 mL) and extracted with DCM (2×50 mL). Drying (Na2SO4) and silica gel flash chromatography (EtOAc/hexane 2:1→2:0) afforded 2-(4-(pent-4-ynyl)piperazin-1-yl)pyrimidine (0.95 g).
Reaction SMILES: CN(C)C=O.[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8](B(O)O)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:26]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[O:30][C:29]([CH3:38])([CH3:37])[CH2:28][N:27]=1>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:37][C:29]1([CH3:38])[CH2:28][N:27]=[C:26]([C:8]2[CH:7]=[N:6][C:15]3[C:10]([CH:9]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[O:30]1
Reactant: CC1(C)CN=C(Cl)c2ccccc2O1
Reactant: OB(O)c1cnc2ccccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)CN=C(c2cnc3ccccc3c2)c2ccccc2O1
Temperature: 90 °C
Reaction time: 14 h
Yield: 52.8 %

Procedure:
After carrying out nitrogen replacement on a dimethylformamide solution (15 mL) of 3-quinoline boronic acid (0.70 g, 4.07 mmol) and 2 M aqueous cesium carbonate solution (4.70 mL, 9.40 mol), tetrakis(triphenylphosphine)palladium (0.72 g, 0.63 mmol) and 5-chloro-2,2-dimethyl-2,3-dihydro-benzo[f][1,4]oxazepine (3.13 mmol) were added to this solution. This solution was then stirred for 14 hours while heating at 90° C. Subsequently, the reaction solution was cooled to room temperature followed by pouring in ethyl acetate (50 mL) and water (50 ml) and filtering with celite. The filtrate was extracted with ethyl acetate (100 mL) and the organic layer was washed with brine (50 mL) followed by drying with magnesium sulfate. After filtering, the solvent was distilled off under reduced pressure to obtain 0.50 g (53%) of the target compound by purifying the resulting residue by silica gel column chromatography (hexane:ethyl acetate=2:1).
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[O:13]1[C:18]2[CH:19]=[CH:20][C:21]([C:23](O)=[O:24])=[CH:22][C:17]=2[O:16][CH2:15][CH2:14]1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:23]([C:21]3[CH:20]=[CH:19][C:18]4[O:13][CH2:14][CH2:15][O:16][C:17]=4[CH:22]=3)=[O:24])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc2c(c1)OCCO2

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 1,4-benzodioxan-6-carboxylic acid (Maybridge) according to methods A and C; yield 49 mg, 0.13 mmol (42%): 1H NMR (300 MHz, methanol-d4) δ 2.08-2.29 (m, 5H), 2.49 (s, 2H), 3.50 (d, J=13 Hz, 2H), 3.56 (s, 2H), 3.85 (d, J=13 Hz, 2H), 4.28 (s, 1H), 7.38-7.50 (m, 2H), 7.87-7.96 (m, 2H), 8.14 (d, J=1 Hz, 1H); MS (DCI/NH3) m/z 315 (M+H)+; Anal. C18H22N2O3.HCl.0.25NH4OH: C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[CH2:21]=[O:22]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[CH2:21][OH:22])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: O=C(c1ccccc1)c1cc(F)ccc1-n1ccnc1
Reactant: C=O
Product: O=C(c1ccccc1)c1cc(F)ccc1-n1ccnc1CO

Procedure:
In the manner given in Example 1, 5-fluoro-2-(imidazol-1-yl)benzophenone is heated in a bomb to 150° C. with 37% aqueous formaldehyde solution to give 5-fluoro-2-[2-(hydroxymethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH3:19][O:20][CH2:21][CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:19][O:20][CH2:21][CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]1[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: COCC1Cc2ccccc2N1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COCC1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 37.2 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 326 mg of 2-(methoxymethyl)indoline and 249 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 162 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 143 mg of 2-{2-[2-(methoxymethyl)-2,3-dihydro-1 H-indol-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a beige powder, the characteristics of which are the following:
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][C:4]([OH:6])=[O:5].[CH2:20](Br)[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22].C(N(CC)CC)C>C(OCC)(=O)C>[OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][C:4]([O:6][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22])=[O:5]
Reactant: CCCCCCCCCCCCCC(O)CC(=O)O
Reactant: O=C(CBr)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCC(O)CC(=O)OCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
To a suspension of (±)-3-hydroxyhexadecanoic acid (500 mg, 1.84 mmol) in ethyl acetate (3.6 ml) were added phenacyl bromide (421 mg, 2.12 mmol) and triethylamine (294 mg, 2.12 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was washed with water, saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, and then dried over magnesium sulfate. Magnesium sulfate was filtered off and the filtrate was concentrated under reduced pressure to obtain 678 mg of the title compound as a pale yellow solid.
Reaction SMILES: C(OC(=O)NC1(C2C=CC(C3C(=O)[C:26]4[C:21](=[CH:22][C:23]([C:29]5[NH:30]N=CC=5)=CC=4)OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C.[C:41]([O:45][C:46](=[O:76])[NH:47][C:48]1([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[C:67](=[O:68])[C:66]4[C:61](=[C:62](Br)[CH:63]=[CH:64][CH:65]=4)[O:60][C:59]=3[C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)=[CH:54][CH:53]=2)[CH2:51][CH2:50][CH2:49]1)([CH3:44])([CH3:43])[CH3:42].N1C=CC=C(B(O)O)C=1>CCOC(C)=O>[C:41]([O:45][C:46](=[O:76])[NH:47][C:48]1([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[C:67](=[O:68])[C:66]4[C:61](=[C:62]([C:23]5[CH:29]=[N:30][CH:26]=[CH:21][CH:22]=5)[CH:63]=[CH:64][CH:65]=4)[O:60][C:59]=3[C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)=[CH:54][CH:53]=2)[CH2:51][CH2:50][CH2:49]1)([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(-c5ccn[nH]5)ccc4c3=O)cc2)CCC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Br)cccc4c3=O)cc2)CCC1
Agent: OB(O)c1cccnc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5cccnc5)cccc4c3=O)cc2)CCC1
Yield: 59 %

Procedure:
Following the procedure used to prepare (1-{4-[4-oxo-2-phenyl-7-(2H-pyrazol-3-yl)-4H-chromen-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester, {1-[4-(8-bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted with pyridine-3-boronic acid to give a crude residue which was insoluble in the EtOAc/aqueous work-up mixture. The solid was collected by filtration and air dried to give the title compound as a tan solid (44 mg, 59%). LCMS (Method B): RT=4.74 min, [M+H]+=545.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][NH:12][O:13][CH3:14].C(N(CC)CC)C.NC1C(N)=NC=CC=1>ClCCl>[CH3:14][O:13][N:12]([CH3:11])[C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CNOC
Agent: Nc1cccnc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-phenylacetyl chloride (commercially available, 4.7 g, 30.5 mmol) in dichloromethane (100 ml) was treated with N,O dimethylhydroxylamine (3.25 g, 33.5 mmol), followed by the addition of triethyl amine (8.5. g 61 mmol) and diaminopyridine (305 mgs). The mixture was stirred at room temperature overnight. The mixture was quenched with water (50 mL) and a saturated solution of ammonium chloride (50 mL). The residue was isolated in a typical aqueous workup and purified by MPLC with 0 to 2% MeOH:CH2Cl2 to give N-methoxy-N-methyl-2-phenylacetamide, (Intermediate 13) (3.5 g 78.7%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:23](Br)[O:22][C:18]=2[N:19]=[CH:20][N:21]=1.[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>CS(C)=O.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>[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:23]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[F:35])[O:22][C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: OB(O)c1ccccc1F
Reactant: COC(=O)CCCCCNc1ncnc2oc(Br)c(-c3ccc(OC)cc3)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3F)c(-c3ccc(OC)cc3)c12
Temperature: 80 °C
Reaction time: 15 h

Procedure:
Add 0.22 ml of a 2 M aqueous sodium carbonate solution to a mixture of 100 mg (0.22 mmol) 6-{[6-bromo-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester and 8 mg (0.01 mmol) bis(triphenylphosphine)palladium(II) chloride in 5.0 ml DMSO. Next, add 39 mg (0.28 mmol) (2-fluorophenyl)boronic acid and stir the mixture for 15 h at 80° C. Filter the reaction mixture and purify directly by preparative RP-HPLC (gradient: water/acetonitrile). 69 mg (29% of theor.) of the desired product is obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][OH:12])=[N:9][CH:10]=1.N1C=CN=C1.CN(C=O)C.[C:23]([Si:27]([CH3:30])([CH3:29])Cl)([CH3:26])([CH3:25])[CH3:24]>C(OCC)(=O)C>[Si:27]([O:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][N:9]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:30])[CH3:29]
Reactant: COCOc1ccc(CO)nc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCOc1ccc(CO[Si](C)(C)C(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a mixture of (5-(methoxymethoxy)pyridin-2-yl)methanol (8.12 g), imidazole (4.90 g) and DMF (50 mL) was added tert-butyldimethylchlorosilane (8.68 g), and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (13.6 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:14]3[O:15][CH2:16][CH2:17][O:18][CH:19]=3)=[CH:12][CH:11]=[C:10]([O:20][CH3:21])[C:8]=2[N:9]=1.[H][H]>O1CCOCC1.C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:22])[NH:4][C:5]1[S:6][C:7]2[C:13]([CH:14]3[CH2:19][O:18][CH2:17][CH2:16][O:15]3)=[CH:12][CH:11]=[C:10]([O:20][CH3:21])[C:8]=2[N:9]=1
Reactant: [H][H]
Reactant: COC(=O)Nc1nc2c(OC)ccc(C3=COCCO3)c2s1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COC(=O)Nc1nc2c(OC)ccc(C3COCCO3)c2s1
Yield: 79.1 %

Procedure:
To a stirred solution of 4.90 g (15.2 mmol) [7-(5,6-dihydro-[1,4]dioxin-2-yl)-4-methoxy-benzothiazol-2-yl]-carbamic acid methyl ester in 250 ml dioxane and 5 ml acetic acid was added 4.9 g of 10% palladium on charcoal and the mixture was then stirred for 24 h at room temperature under a 10 bar atmosphere of hydrogen. The mixture was then filtered, washing with dioxane, and the filtrate concentrated in vacuo. Trituration in acetone afforded 3.90 g (79%) (±)-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester as a white solid. ES-MS m/e (%): 325 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6]([Cl:15])[N:5]=[CH:4][N:3]=1.[K+].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH-:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].O>CS(C)=O>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:30][C:2]2[C:7]([C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)=[C:6]([Cl:15])[N:5]=[CH:4][N:3]=2)(=[O:28])=[O:29])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(S([NH-])(=O)=O)cc1
Reactant: Cc1ccc(-c2c(Cl)ncnc2Cl)cc1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.3 %

Procedure:
A mixture of 0.8 g of 4,6-dichloro-5-(p-tolyl)-pyrimidine and 1.68 g of 4-tert.-butylbenzene sulfonamide potassium salt (Example 2a) in 20 ml of DMSO was stirred at room temperature for 24 h. The mixture was poured onto 200 ml of water and extracted twice with 100 ml of diethyl ether. The organic layers were extracted twice with 50 ml of water. The combined aqueous layers were acidified hydrochloric acid. The resulting fine suspension was extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4 and evaporated. The residue was dried under high vacuum to give 1.34 g 4-tert.-butyl-N-[6-chloro-5-(p-tolyl)-4-pyrimidinyl]-benzene sulfonamide as a white powder. LC-MS: tR=5.92 min, [M+1]+=416.20, [M−1]−=414.24.
Reaction SMILES: [C:1]12([CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)[C:10]1[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:4](=O)[CH2:3][CH2:2]2.O.NN.[OH-].[K+]>C(O)CO>[C:1]12([CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)[C:10]1[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:4][CH2:3][CH2:2]2
Reactant: O=C1CCC2(CC1)CCC(=O)c1ccccc12
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: O=C1CCC2(CCCc3ccccc32)CC1
Reaction time: 18 h
Yield: 69.5 %

Procedure:
A solution of 3.63 g. (0.0115 M) of spiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione, 4-(2,2-dimethyltrimethylene ketal(p) (prepared as in Example 14A), 1.54 ml. of hydrazine hydrate and 2.23 g. of potassium hydroxide in 28 ml. of ethylene glycol is heated to reflux. Distillate is collected until the pot temperature rises to 200° C. and refluxing is continued for about 18 hours. The mixture is poured into water and a precipitated material is extracted with ether. The combined extracts are washed with water and brine and then evaporated to dryness. The residue is recrystallized from petroleum ether to give 2.39 g. (69.5% yield) of 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalene]-4-one, 2,2-dimethyltrimethylene ketal(q) having a melting point of 109° to 111° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:10]=[N:9][N:8]([CH:11]3[CH:15]4[O:16][C:17]([CH3:20])([CH3:19])[O:18][CH:14]4[CH:13]([CH2:21][OH:22])[O:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C[Si](Cl)(C)C.[C:28](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29].[NH4+].[OH-]>N1C=CC=CC=1>[OH:22][CH2:21][CH:13]1[CH:14]2[O:18][C:17]([CH3:19])([CH3:20])[O:16][CH:15]2[CH:11]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:1][C:28](=[O:29])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:3]=3[N:10]=[N:9]2)[O:12]1
Reactant: CC1(C)OC2C(CO)OC(n3nnc4c(N)ncnc43)C2O1
Reactant: O=C(Cl)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CC1(C)OC2C(CO)OC(n3nnc4c(NC(=O)c5ccccc5)ncnc43)C2O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
Compound 6.2 (2.2 g, 7.14 mmol) was dissolved in 30 mL pyridine and cooled to 0° C. To this was added TMSCl (2.7 mL, 21.4 mmol). The mixture was stirred at 0° C. for 30 min and then treated with BzCl (4.95 mL, 35.7 mmol). The mixture was stirred at 0° C. for 3 h and then treated with NH4OH (7.3 mL), stirred at 0° C. for another 30 min. The mixture was concentrated under reduced pressure and the residue was partitioned between CH2Cl2 and 1N HCl. The water layer was extracted three times with CH2Cl2. The organic layer was combined, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography eluting with 80% EtOAc in Hexane to yield compound 6.3 (1.84 g, 63% yield). 1HNMR (300 MHz, CDCl3) δ 1.42 (s, 3H), 1.70 (s, 3H), 3.79-4.01 (m, 2H), 4.63 (s, 1H), 5.14-5.16 (m, 1H), 5.31-5.35 (m, 1H), 6.68 (d, 1H, J=4.2), 7.55-7.61 (m, 2H), 7.61-7.69 (m, 1H), 8.08 (d, 2H, J=7.2), 8.90 (s, 1H). LRMS (ESI) MH+ C19H20N6O5 requires 413.2. Found 412.9.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]2[N:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:20]=[C:21]([CH3:22])[C:10]=12>O1CCCC1>[CH2:1]([O:5][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]2[N:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:20]=[C:21]([CH3:22])[C:10]=12)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: Cc1nn(-c2ccccn2)c2nc3ccccc3c(Cl)c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOc1c2ccccc2nc2c1c(C)nn2-c1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 25.7 %

Procedure:
To an ice-cold solution of 1-butanol (5.0 g, 68 mmol) in tetrahydrofuran (15 mL), sodium hydride (oiliness, content 60%, 0.41 g, 17 mmol) was added at room temperature and the mixture was stirred for 15 minutes. Subsequently, 4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.0 g, 3.39 mmol) was added to the mixture at 0° C., and the mixture was heated under reflux for another 1 hour. After the reaction solution was cooled to room temperature, the reaction solvent was concentrated and evaporated under reduced pressure. To the reaction mixture was added iced water and the mixture was neutralized by the addition of dilute hydrochloric acid, and the organic matter was extracted with ethyl acetate. The extract was washed with saturated brine and water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (ethyl acetate) to give the title compound (0.29 g, 26% yield).
Reaction SMILES: C1(S([NH2:10])(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17]([C:19]1([CH2:28][CH3:29])[CH2:24][CH2:23][CH:22]([N:25]=[C:26]=[O:27])[CH2:21][CH2:20]1)[CH3:18].O>O1CCOCC1>[CH2:28]([C:19]1([CH2:17][CH3:18])[CH2:20][CH2:21][CH:22]([NH:25][C:26](=[O:27])[NH2:10])[CH2:23][CH2:24]1)[CH3:29]
Reactant: CCC1(CC)CCC(N=C=O)CC1
Reactant: NS(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCC1(CC)CCC(NC(N)=O)CC1
Reaction time: 2 h

Procedure:
9.6 g of 4-(β-<2-methoxy-5-chlorobenzamido>α-methylethyl)-benzenesulfonamide are dissolved in 250 ml of dioxane. 6.9 g of finely ground potassium carbonate are added and the whole is heated to boil for 2 hours while stirring. 4.5 g of 4.4-diethylcyclohexyl-isocyanate are added dropwise while continuing to stir. Stirring and heating is continued for 8 hours, the whole is poured into water and acidified. The crystalline precipitate obtained is filtered off with suction and dried. The whole is dissolved in dimethylformamide, methanol is added and thus a crystalline mass is obtained of N-[4-(β-<2-methoxy-5-chlorobenzamido>α-methyl)-ethyl-benzenesulfonyl]-N'-(4.4-diethyl-cyclohexyl)-urea melting at 161°-163°C.