Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[N:28]=[C:29]([C:33]4[O:34][CH:35]=[CH:36][CH:37]=4)[O:30][C:31]=3[CH3:32])=[C:21]([O:38][CH3:39])[CH:20]=2)=[N:8][N:9]([CH2:11][C:12](OCC)=[O:13])[CH:10]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[O:34]1[CH:35]=[CH:36][CH:37]=[C:33]1[C:29]1[O:30][C:31]([CH3:32])=[C:27]([CH2:26][O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:7]3[C:6]([CH2:4][OH:3])=[CH:10][N:9]([CH2:11][CH2:12][OH:13])[N:8]=3)=[CH:20][C:21]=2[O:38][CH3:39])[N:28]=1
Reactant: CCOC(=O)Cn1cc(C(=O)OCC)c(OCc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(COc2nn(CCO)cc2CO)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
To a solution of ethyl {4-ethoxycarbonyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazol-1-yl}acetate (1.24 g) in tetrahydrofuran (30 mL) was added lithium aluminum hydride (0.17 g) at 0° C. and the mixture was stirred at room temperature for 1 hr. Sodium sulfate decahydrate (1.48 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and the precipitate was filtered off. The filtrate was concentrated to give 2-[3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-4-(hydroxymethyl)-1H-pyrazol-1-yl]ethanol as colorless crystals (0.73 g, yield 70%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 120-122° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([CH3:19])=[C:11](Cl)[C:12]([F:17])=[CH:13]2)=[C:8]([CH:20]2[CH2:22][CH2:21]2)[CH:7]=1)=[O:5])C.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(#N)C>[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:30][CH2:31][N:32]([C:11]2[C:12]([F:17])=[CH:13][N:14]3[C:9]([C:10]=2[CH3:19])=[C:8]([CH:20]2[CH2:22][CH2:21]2)[CH:7]=[C:6]([C:4]([OH:3])=[O:5])[C:15]3=[O:16])[CH2:33][CH2:34]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Solvent: CC#N
Product: Cc1c(N2CCN(c3ccccn3)CC2)c(F)cn2c(=O)c(C(=O)O)cc(C3CC3)c12

Procedure:
A 60 mg sample of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in 2 mL of anhydrous acetonitrile, reacted with 4-(2-pyridyl)piperazine (63.5 mg, 0.39 mmol, Aldrich Chem. Co.), and carried forward as described in Example 253j-k to give the title product. MS 423 (M+H)+ ; 1H NMR (CDCl3) δ: 0.71 (m, 2H), 1.05 (m, 2H), 2.30 (m, 1H), 2.86 (s, 3H), 3.59 (m, 4H), 3.78 (m, 4H), 6.76 (m, 2H), 7.57 (m, 1H), 8.25 (m, 1H), 8.40 (s, 1H), 8.25 (d, 1H), 13.83 (bs, 1H). Anal. Calcd for C23H23N4O3F.1.5H2O: C, 61.46; H, 5.83; N, 12.46; Found: C, 61.76; H, 5.54; N, 11.64.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li]CCCC.[CH:15]1([C:21]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([O:25][Si](C)(C)C)[C:22](=[O:24])[CH3:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[Br:36][CH2:37][C:38]#[C:39][CH2:40]Br.Cl>C1COCC1.CCOCC.CO.O.C(O)(=O)C>[CH:15]1([C:21]([OH:25])([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:22](=[O:24])[CH2:23][CH2:40][C:39]#[C:38][CH2:37][Br:36])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: BrCC#CCBr
Reactant: CC(=O)C(O[Si](C)(C)C)(c1ccccc1)C1CCCCC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(CCC#CCBr)C(O)(c1ccccc1)C1CCCCC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
To a dry flask under argon was added 1,1,1,3,3,3-hexamethyldisilazane (11.6 g, 71.6 mmole) and 75 ml of THF. The solution was cooled to -10° C. and n-BuLi (19.8 g, 71.3 mmol) was added directly to the reaction mixture. The solution was stirred at -10° C. for 30 minutes. A solution of 1-cyclohexyl-1-phenyl-1-trimethylsilyloxypropan-2-one (21.99 g, 72.2 mmol) in dry THF (75 ml) was added dropwise over a period of 15 minutes and the reaction mixture was stirred at -10° C. After the solution had stirred for 1 hour 1,4-dibromo-2-butyne (59.9 g, 0.3 mole) was added directly to the reaction mixture and the mixture was stirred an additional hour. The reaction was stopped by the dropwise addition of a solution of glacial acetic acid (7 ml) in ether (20 ml). The solution was warmed to room temperature and ether (150 ml) was added. The solution was washed with water followed by a saturated aqueous sodium chloride solution. The ether layer was dried and concentrated to afford a brownish liquid. This oil was dissolved in 150 ml of methanol and 0.2 ml of concentrated hydrochloric acid was added. The solution was stirred at 40° C. for 30 minutes and cooled to room temperature. Water was then added until the solution became cloudy and then 150 ml of ether was added. The solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and evaporated under vacuum to afford a yellowish brown oil. Purification on a silica column with a hexane:ethyl acetate solution (98:2 followed by 9:1) afforded an orange oil (16.1 g, 59.5%). NMR (CDCl3) δ7.6-7.2(m, 5H), 4.3(s, 1H), 3.8(t, 2H), 2.8-2.6 (m, 2H), 2.5-2.3(m, 2H), 1.9-1.1(m, 11H). IR (neat) 3461, 2234, 1705, 609 cm-1. TLC (silica, petroleum ether:ethyl acetate (95:5)) Rf=0.53.
Reaction SMILES: [CH3:1][CH:2]1[NH:8][CH2:7][C:6]2[CH:9]=[CH:10][C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:12][C:5]=2[O:4][CH2:3]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:30](C)=O.[Na+].O>C(O)(=O)C.C(Cl)Cl>[CH3:1][CH:2]1[N:8]([CH3:30])[CH2:7][C:6]2[CH:9]=[CH:10][C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:15][CH2:14]3)=[N:12][C:5]=2[O:4][CH2:3]1
Reactant: CC1COc2nc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2CN1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: CC1COc2nc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2CN1C
Temperature: 25 °C
Reaction time: 25 h
Yield: 39.1 %

Procedure:
To a solution of the compound (0.30 g) obtained in Example 22 and paraformaldehyde (0.052 g) in a mixture of acetic acid (0.20 mL) and CH2Cl2 (4 mL) was added NaBH(OAc)3 (0.274 g), and the mixture was stirred at room temperature for 25 hr. Paraformaldehyde (0.052 g) and NaBH(OAc)3 (0.274 g) were further added, and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into water, and the resultant product was extracted with CH2Cl2. The organic layer was washed with water and brine, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 30→60% ethyl acetate/hexane) to give the title compound (0.122 g, 39%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH:5]=O.C([CH2:16][S:17]([CH2:20][S:21]([CH2:24][C:25](O)=O)(=[O:23])=[O:22])(=[O:19])=[O:18])(O)=O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1/[CH:5]=[CH:16]/[S:17]([CH2:20][S:21](/[CH:24]=[CH:25]/[C:4]1[C:3]([O:2][CH3:1])=[CH:10][CH:9]=[CH:8][C:7]=1[O:11][CH3:12])(=[O:22])=[O:23])(=[O:18])=[O:19]
Reactant: COc1cccc(OC)c1C=O
Reactant: O=C(O)CS(=O)(=O)CS(=O)(=O)CC(=O)O
Solvent: CC(=O)O
Product: COc1cccc(OC)c1/C=C/S(=O)(=O)CS(=O)(=O)/C=C/c1c(OC)cccc1OC
Yield: 74 %

Procedure:
A solution of 2,6-dimethoxybenzaldehyde (2 mmol) and carboxymethane-sulfonylmethanesulfonyl-acetic acid (1 mmol) in acetic acid (10 mL) was subjected to General Procedure 1, to yield the title compound in 74% yield. m.p. 118-120° C.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9])=[O:5].S(Cl)([Cl:23])=O>ClCCl.CN(C=O)C>[F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:7]=1[C:8]([Cl:23])=[O:9])=[O:5]
Reactant: COc1ccc(C(=O)O)c(C(=O)c2ccccc2F)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)Cl)c(C(=O)c2ccccc2F)c1
Reaction time: 1 h

Procedure:
To a solution of 2-2-fluorobenzoyl)-4-methoxybenzoic acid (84) (2.05 g, 7.48 mmol) in 50 mL of dichloromethane was added thionyl chloride (2.40 mL, 14.9 mmol), followed by 3 drops of DMF. The reaction was warmed to reflux. After 1 hour, LC-MS (aliquot quenched with pyrrolidine/ACN/H2O) showed that the reaction was complete (ESI+MS for corresponding pyrrolidine amide: 328.2 [M+H]+). The reaction was concentrated in vacuo to provide an oil which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]>CCOC(C)=O.[Pd]>[NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1cccc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CNC(=O)c1cccc(N)c1N
Yield: 0.1 %

Procedure:
2-Amino-N-methyl-3-nitro-benzamide (1.4 g, 7.2 mmol) was reduced by hydrogenation using 50 psi of H2 with 10% Pd—C (250 mg) in EtOAc (25 mL) for 5 h. After filtering through Celite, solvent was removed in vacuo. Purification by silica gel chromatography (10% MeOH/CHCl3) gave 1.08 mg (91%) of 2,3-diamino-N-methyl-benzamide as a faintly yellow solid. 1H NMR (300 MHz, CDCl3) δ 6.87 (dd, 1H, J=7.8, 1.5 Hz), 6.76 (dd, 1H, J=7.8, 1.5 Hz), 6.59 (t, 1H, J=7.8 Hz), 6.14 (br s, 1H), 4.28 (br s, 4H), 2.95 (d, 3H, J=5.1 Hz).
Reaction SMILES: [K].[CH3:2][C:3]1([CH3:10])[NH:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].[C:11]1([C:21](Cl)=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.C(OCC)(=O)C>O1CCCC1>[CH3:2][C:3]1([CH3:10])[NH:7][C:6](=[O:8])[N:5]([C:21]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[O:22])[C:4]1=[O:9]
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CC1(C)NC(=O)NC1=O
Agent: [K]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)NC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.2 %

Procedure:
5,5-Dimethylimidazolidine-2,4-dione potassium salt (1.47 g) was suspended in tetrahydrofuran (5 mL), 1-naphthoyl chloride (1.46 g) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (50 mL) was added to the reaction solution, and the mixture was filtered with a membrane filter (0.25 μm). The resulting organic layer was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to obtain 674 mg of white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]([CH2:7][N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16](=[O:27])/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:10][CH2:9]1)=[CH2:6])[CH3:2].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([CH2:6][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:7][N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16](=[O:27])/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:10][CH2:9]1)[CH3:2]
Reactant: C1CCNCC1
Reactant: C=C(CN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(CN1CCCCC1)CN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Temperature: 25 °C
Yield: 44.8 %

Procedure:
A suspension of 0.80 g (1.88 mmol) of 2-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-ylmethyl}-acrylic acid ethyl ester, 0.56 ml (5.64 mmol) of piperidine and 1.83 g (5.61 mmol) of cesium carbonate in 32 ml of acetonitrile was stirred over night at RT. Additional 0.37 ml (3.76 mmol) of piperidine were added and after 1 h, cesium carbonate was filtrated and the solvent evaporated. Purification by flash silica gel column (CH2Cl2/MeOH 98:2 to 96:4) gave 0.43 g (44%) of the title compound as colorless foam. MS: 510.4 (MH+, 2Cl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[N:29]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>[Cu]I.CS(C)=O>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[N:8]([CH2:7][C:6]4[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:9]=[C:10]([N:32]4[CH2:31][CH2:30][N:29]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][CH2:33]4)[C:11]=23)=[C:19]([F:25])[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COc1ccc(Cn2nc(N3CCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 56.7 %

Procedure:
A 100 mL round-bottomed flask was charged with 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (100.0 mg, 0.2040 mmol, prepared in Example 7, step B), tert-butyl piperazine-1-carboxylate (114.0 mg, 0.6119 mmol), copper(I)iodide (7.769 mg, 0.04079 mmol), (S)-pyrrolidine-2-carboxylic acid (9.393 mg, 0.08159 mmol), K2CO3 (140.9 mg, 1.020 mmol) and DMSO (10 mL). The reaction mixture was stirred at 100° C. for 4 hours. The reaction was cooled to room temperature and partitioned between EtOAc and H2O. The phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude material was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford product (63.5 mg, 56.75%). LRMS (APCI pos) m/e 549 (M+1).
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]([CH2:16][C:17]([O:19]CC)=[O:18])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]([CH2:16][C:17]([OH:19])=[O:18])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC1CC(c2ccccc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC1CC(c2ccccc2)c2ccccc21

Procedure:
3-Phenyl-1-indanone (83 g, 0.4 mol) was dried by refluxing in C6H6 (120 ml) with removal of the azeotroped H2O. To this solution was added Et2O (120 ml) and Zn wool (26.25 g, 0.4 mol). The reaction mixture was heated to near reflux and a crystal of I2 added. Ethyl bromoacetate (110 g, 0.6 mol) was added over 2 hours, the temperature being kept near reflux by heat of reaction and some external heating. After the addition, the mixture was stirred and refluxed for a further 0.5 hour, cooled and poured into ice and acetic acid. The mixture was extracted with Et2O. The Et2O was washed with 1% NH4OH, dried (Na2SO4), filtered and evaporated and the residue distilled to give a mixture of ethyl 3-phenylindene-1-acetate and its corresponding double bond isomer (83.6g) b.p. 145°-155° C. (0.1 mm). This mixture of esters was hydrogenated over 10% Pd/C (0.6g) to give ethyl 3-phenylindan-1-acetate. This ester was hydrolyzed by refluxing with sodium hydroxide in ethanol to give the title compound, m.p. 126°-9° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:9]([O:10][CH2:11][CH2:12][CH3:13])=[CH:8][S:7][CH:6]=1)CC.C(O)C(O)CC[OH:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[O:10]1[CH:11]([CH2:12][CH2:13][OH:18])[CH2:1][O:4][C:5]2=[CH:6][S:7][CH:8]=[C:9]12
Reactant: CCCOc1cscc1OCCC
Reactant: OCCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: OCCC1COc2cscc2O1

Procedure:
9.06 g (45.2 mmol) of 3,4-di-n-propoxythiophene, 24.0 g (226 mmol) of 1,2,4-butanetriol and 0.09 g (0.5 mmol) of p-toluenesulphonic acid were heated to 150 to 160° C. (bath temperature) under N2 for 2 h. During this time, 5.89 g of distillate (substantially n-propanol) were collected. The cooled liquid was diluted with 50 ml of methylene chloride, washed to neutrality with water and the organic phase was dried over Na2SO4. After filtering and evaporating the methylene chloride at 1 mbar, distillation was then effected. According to 1H NMR spectroscopy, the fraction collected between 45 and 128° C. (1.63 g=19.4% of overall theoretical yield of transetherification products) consisted of approx. 81.5% of 2-(2,3-dihydrothieno[3,4-b][1,4]dioxin-2-yl)ethanol, 6.5% of 3,4-dihydro-2H-thieno[3,4-b][1,4]dioxepin-2-ylmethanol and 12% of 2,3,4,5-tetrahydrothieno[3,4-b][1,4]dioxocin-3-ol.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:13][C:14](=[O:19])[CH2:15][C:16](=[O:18])[CH3:17]>>[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[C:15]([C:14](=[O:19])[CH3:13])[C:16](=[O:18])[CH3:17])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Reactant: CC(=O)CC(C)=O
Product: CC(=O)C(=Cc1ccc(S(C)(=O)=O)cc1)C(C)=O

Procedure:
The procedure described in Example 1 was repeated by using 1.1 g of 4-methylsulfonylbenzaldehyde and 1.5 g of 2,4-pentanedione. The product was crystallized from ether, mp 139°-140° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[CH:17][C:6]([CH2:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[CH:5][CH:4]=1)[CH3:2].S(=O)(=O)(O)O>O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C:8]3[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=[O:12])[C:17]=2[CH:18]=1)[CH3:2]
Reactant: CCc1ccc(Cc2ccccc2C(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCc1ccc2c(c1)C(=O)c1ccccc1C2
Reaction time: 3 h

Procedure:
2-(4-Ethylbenzyl)benzoic acid (14 g) is added with stirring to sulphuric acid (200 ml) at 0° C. After 3 hours, the solution is poured into water and the product is extracted with ethyl acetate. The extract is washed with aqueous sodium carbonate, then dried and evaporated, to yield 2-ethylanthrone.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([S:20](Cl)(=[O:22])=[O:21])[N:19]=[C:6]2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:4]=1[CH3:34])#[N:2].CN.[CH2:37]([N:39](CC)CC)C>C1COCC1>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([S:20]([NH:39][CH3:37])(=[O:22])=[O:21])[N:19]=[C:6]2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:4]=1[CH3:34])#[N:2]
Reactant: CCN(CC)CC
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(S(=O)(=O)Cl)nc2N1c1cccc(C(F)(F)F)c1
Agent: CN
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon, abs. THF (3 ml) was stirred with molecular sieve (4 Å, 30 mg) for 30 min (7R)-6-Cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonyl chloride (63%, 50 mg, 62 μmol), methylamine (2 M solution in THF; 94 μl, 0.19 mmol, 3 eq.) and triethylamine (9 μl, 62 μmol, 1 eq.) were added and the mixture was stirred at RT for 12 h. The reaction solution was then concentrated under reduced pressure and the residue was purified by preparative HPLC (Reprosil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (23 mg, 73% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([CH2:23][CH2:24]Cl)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1.[NH:28]1[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29]1>CC#N>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([CH2:23][CH2:24][N:28]3[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1
Reactant: OC1CCNC1
Reactant: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2CCCl)c2cnccc12
Solvent: CC#N
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2CCN2CCC(O)C2)c2cnccc12
Yield: 6 %

Procedure:
A solution of 1-{[5-chloro-1-(2-chloroethyl)-1H-benzimidazol-2-yl]methyl}-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine (110 mg, 0.26 mmol) and 3-pyrrolidinol (1 mL) in CH3CN (2 mL) was heated at 150° C. for 1 hour under microwave irradiation. The resulting mixture was concentrated in vacuo and the residue was purified by column chromatography (MeOH:DCM=3:25) to afford the title product as a grey solid (8 mg, yield: 6%).
Reaction SMILES: [P:1]([O-:47])([O-:46])([O:3][C:4](C(C)(C)C)(C(C)(C)C)[N:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:36])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[O:34][CH3:35])=[CH:7][C:6]1=[O:37])=[O:2]>CC#N.O.CC(O)=O>[P:1]([OH:46])([OH:47])([O:3][CH2:4][N:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:36])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:24])([F:25])[C:20]([F:22])([F:23])[F:21])=[CH:15][C:14]=2[O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[O:34][CH3:35])=[CH:7][C:6]1=[O:37])=[O:2]
Reactant: COc1cc(F)ccc1Oc1cc(C(F)(F)C(F)(F)F)ccc1C(=O)Nc1ccn(C(OP(=O)([O-])[O-])(C(C)(C)C)C(C)(C)C)c(=O)c1
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(F)ccc1Oc1cc(C(F)(F)C(F)(F)F)ccc1C(=O)Nc1ccn(COP(=O)(O)O)c(=O)c1
Yield: 43.9 %

Procedure:
A solution of ditert-butyl[4-[[2-(4-fluoro-2-methoxy-phenoxy)-4-(1,1,2,2,2-pentafluoroethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl phosphate (21) (35 mg, 0.05039 mmol) in CH3CN (700.0 μL), water (700.0 μL) and AcOH (700.0 μL) was refluxed for 1 hour then evaporated to dryness. The material was then co-evaporated with CH3CN (3×), triturated with CH3CN, filtered, washed with CH3CN and desiccated to give [4-[[2-(4-fluoro-2-methoxy-phenoxy)-4-(1,1,2,2,2-pentafluoroethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate (2) (13 mg, 0.02210 mmol, 43.9%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 7.31 (dd, J=8.9, 5.9 Hz, 1H), 7.16 (dd, J=10.7, 2.9 Hz, 1H), 6.94 (d, J=1.9 Hz, 1H), 6.91-6.84 (m, 1H), 6.77 (s, 1H), 6.47 (dd, J=7.6, 2.2 Hz, 1H), 5.54 (d, J=9.7 Hz, 2H), 3.74 (s, 3H) ppm. 31P NMR (162 MHz, DMSO-d6-85% H3PO4 aq. as internal standard—0 ppm) δ −1.93 (t, J=9.7 Hz, 1H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[F:15][C:16]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[C:17]=1[NH2:18].N1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:12])(=[O:11])[NH:18][C:17]2[C:16]([F:15])=[CH:22][C:21]([F:23])=[CH:20][C:19]=2[F:24])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1c(F)cc(F)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(S(=O)(=O)Nc2c(F)cc(F)cc2F)cc1
Temperature: -50 °C

Procedure:
2.35 g (10 mmol) of 4-chlorosulfonyl-benzoic acid methyl ester is suspended in 30 ml of dichloromethane with exclusion of moisture, the suspension is cooled to -50° C and, at this temperature, a solution of 1.47 g (10 mmol) of 2,4,6-trifluoroaniline and 1 ml of pyridine in 20 ml of dichloromethane is instilled. When the instillation is completed, it is allowed to come to room temperature and stirred for 12 more hours. The resulting precipitate is suctioned off and extracted with ether. The ether extract and the filtrate together are concentrated by evaporation, the residue is dissolved in dichloroethane and chromatographed on silica gel 60 (Merck) with ethyl acetate/hexane. 2.71 g (7.96 mmol)=78.6% of the theoretical yield is obtained as a partially crystalline, partially amorphous product.