Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([O:18][C@@H:19]1[C@H:26]2[C@H:22]([O:23][C:24]([CH3:28])([CH3:27])[O:25]2)[C:21]([CH2:29][O:30][C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:20]1I)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].C[O:52][B:53](OC)[O:54]C>C1COCC1>[Si:5]([O:18][C@@H:19]1[C@@H:26]2[O:25][C:24]([CH3:27])([CH3:28])[O:23][C@@H:22]2[C:21]([CH2:29][O:30][C:31]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[C:20]1[B:53]([OH:54])[OH:52])([C:1]([CH3:4])([CH3:2])[CH3:3])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC1(C)O[C@@H]2[C@H](O1)C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)=C(I)[C@@H]2O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: COB(OC)OC
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2[C@H](O1)C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)=C(B(O)O)[C@@H]2O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 100 mL round-bottom 3-neck flask equipped with nitrogen inlet/outlet, stir bar, and thermocouple with temperature controller was charged 3.0877 g of compound 8 (3 mmol, 1.0 eq) and 30 mL tetrahydrofuran (10 V). Reaction was cooled to 0° C. To this solution was added 6.98 mL (9 mmol, 2.4 eq) of isopropylmagnesium chloride lithium chloride complex, 1.3 M in THF slowly over 15 minutes. The reaction was stirred at 0° C. for 1 hour. An HPLC assay indicated the formation of intermediate. 1.05 mL of trimethylborate (9 mmol, 2.5 eq) was added to the reaction. An HPLC assay after 1 hour at 0° C. indicated that the reaction was completed. Quenched reaction with saturated aqueous ammonium chloride solution (3V). The ice bath was removed and the reaction was warmed to room temperature. The reaction was charged with DI water (3V) and ethyl acetate (6V). The layers were separated and the aqueous layer was back-extracted with ethyl acetate (6V). The organic phases were combined and washed with brine (3V) and dried over MgSO4. The resulting mixture was filtered. The filtrate was concentrated to dryness with a rotary evaporator. Obtained 2.87 grams (100% crude yield), 96 A % purity of [(3aR,6S,6aR)-6-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-4-(trityloxymethyl)-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-5-yl]boronic acid (compound 9c-1).
Reaction SMILES: [F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([CH:8]([CH:18]([CH3:20])[CH3:19])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28]([CH3:34])=[N:29]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([CH:8]([CH:18]([CH3:20])[CH3:19])[CH2:9][C:10]([C:13]([F:15])([F:14])[F:16])([OH:17])[CH:11]=[N:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][C:28]([CH3:34])=[N:29]3)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(F)cccc1C(CC(O)(C=O)C(F)(F)F)C(C)C
Reactant: Cc1ccc2c(N)cccc2n1
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1c(F)cccc1C(CC(O)(C=Nc1cccc2nc(C)ccc12)C(F)(F)F)C(C)C

Procedure:
In the same way as in Example 61, 200 mg (0.62 mmol) of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-5-methyl-2-(trifluoromethyl)hexanal, 125 mg (0.80 mmol) of 5-amino-2-methylquinoline and 0.3 ml of titanium tetraethoxide are reacted to give 4-(3-fluoro-2-methoxyphenyl)-1-[(2-methylquinolin-5-yl)imino]-5-methyl-2-(trifluoromethyl)hexan-2-ol. 229 mg of imine purified by column chromatography (silica gel, hexane/ethyl acetate 0-35%) are cyclized in the same way as in Example 61 at −20° C. with 5 ml (5 mmol) of 1 M boron tribromide solution in dichloromethane to give the desired product. Column chromatography on silica gel (hexane/2-propanol 0-15%) and subsequent preparative HPLC (SunFire C18, water/methanol) yield 11 mg of product.
Reaction SMILES: C(NC(C)C)(C)C.O1CCCC1.C([Li])CCC.[Br:18][C:19]1[S:20][CH:21]=[C:22]([Br:24])[N:23]=1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[Br:18][C:19]1[S:20][C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:22]([Br:24])[N:23]=1
Reactant: CCOC(=O)Cl
Reactant: Brc1csc(Br)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1sc(Br)nc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
In a 50 mL 2-neck RBF equipped with septa, a solution of N,N-Diisopropylamine (0.04374 g, 0.4322 mmol) in tetrahydrofuran (1.33 mL, 16.4 mmol) under atmosphere of argon was cooled at −78° C., at which point n-butyllithium (2.50 M in hexane, 0.1647 mL, 0.4116 mmol) was added dropwise and the resulting solution was stirred for 30 minutes at −78° C. To the above solution was added dropwise a solution of 2,4-dibromothiazole (0.100 g, 0.412 mmol) in tetrahydrofuran (1.33 mL, 16.4 mmol) at −78° C., and this solution was stirred for 30 min −78. Next, ethyl chloroformate (0.07872 mL, 0.8233 mmol) was added dropwise at −78° C. and the mixture was stirred for 30 minutes. The reaction was quenched by addition of water (20 mL), the layers were separated, and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via silica gel column chromatography (12 g Analogix column, gradient elution 5% to 10% EtOAc in hexane) to afford ethyl 2,4-dibromo-1,3-thiazole-5-carboxylate (60 mg, yield 46%). LC/MS: (FA) ES+ 314, 316, 318; 1H NMR (400 MHz, CDCl3) δ 4.37 (q, J=7.1, 2H), 1.44-1.33 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH2:13][CH2:12][N:11]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:15])[CH2:10][CH2:9]3.[F:29][C:30]1[CH:31]=[C:32]([S:37](Cl)(=[O:39])=[O:38])[CH:33]=[C:34]([F:36])[CH:35]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH2:9][CH2:10][N:11]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[N:18]([S:37]([C:32]2[CH:31]=[C:30]([F:29])[CH:35]=[C:34]([F:36])[CH:33]=2)(=[O:39])=[O:38])[CH:17]=1)=[O:15])[CH2:12][CH2:13]3
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(Br)cc21
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Product: O=C1OC2(CCN(C(=O)c3cn(S(=O)(=O)c4cc(F)cc(F)c4)c4cc(Cl)ccc34)CC2)c2ccc(Br)cc21

Procedure:
Following the general procedure VII as described above, the sulphonylation of 5-bromo-1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one with commercially available 3,5-difluorobenzenesulfonyl chloride gave the title compound.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Cl[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1>>[N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[CH2:23][N:8]1[C:9]([C:10](=[O:19])[C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]1=[O:20]
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: ClCc1ccc2ccccc2n1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccc3ccccc3n2)c1
Yield: 39.8 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 2-chloromethyl quinoline were reacted by the same way with the example 1 to obtain the titled compound (170 mg, yield: 39.8%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])[CH:5]=[CH:6][CH:7]=1.S(OC)(O[CH3:21])(=O)=O>[OH-].[Na+]>[CH3:21][O:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: COS(=O)(=O)OC
Reactant: CN1CCCCC(c2cccc(O)c2)C1=O
Agent: [Na+]
Agent: [OH-]
Product: COc1cccc(C2CCCCN(C)C2=O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.9 %

Procedure:
Hexahydro-3-(3-hydroxyphenyl)-1-methyl-2H-azepin-2-one (21.9 g) was dissolved in 2 M sodium hydroxide solution (100 ml) and dimethyl sulphate (18.3 g, 14.5 ml) added. The reaction mixture was stirred at room temperature for 10 minutes then seeded. The product crystallised after leaving at 0° C. for 3 hours. The product was filtered, washed with water and dried affording 16.99 g of title compound as off-white powder m.p. 73°-74° C., identical to that obtained in Example 2.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17].C(N(CC)CC)C.Br[CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40]>O1CCCC1>[CH3:1][N:2]([CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:8](=[O:17])[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15]1=[O:16]
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: CNCCCCN1C(=O)c2ccccc2C1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(CCCCN1C(=O)c2ccccc2C1=O)CCCCN1C(=O)c2ccccc2C1=O
Temperature: 165 °C

Procedure:
209 mg (0.9 mmol) of 2-[4-(methylamino)butyl]-1H-isoindole-1.3(2H)-dione is solubilized in 5 ml of tetrahydrofuran, then 385 μl (2.7 mmol; 3 equivalents) of triethylamine and 254 mg (0.9 mmol; 1 equivalent) of 2-(4-bromobutyl)-1H-isoindole-1.3(2H)-dione are added to the reaction mixture which is maintained for 25 minutes under microwaves at 165° C. The precipitate obtained is filtered and the filtrate concentrated under reduced pressure. The expected product is purified by chromatography on a silica column (eluent: dichloromethane/methanol: 95/5).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[CH3:10][CH:11]1[CH:16](O)[CH2:15][CH2:14][N:13]([C:18]2[N:19]=[N:20][CH:21]=[CH:22][N:23]=2)[CH2:12]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH:16]1[CH2:15][CH2:14][N:13]([C:18]2[N:19]=[N:20][CH:21]=[CH:22][N:23]=2)[CH2:12][CH:11]1[CH3:10]
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: CC1CN(c2nccnn2)CCC1O
Product: CC1CN(c2nccnn2)CCC1Oc1cc(Cl)ccc1Cl

Procedure:
Compound 38 is prepared from 2,5-dichlorophenol and intermediate 5c according to synthesis method 3 under the operating conditions described for example 8 (37% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.C(N(CC)CC)C.[C:25](Cl)(=[O:29])[CH:26]([CH3:28])[CH3:27]>ClCCl>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: CC(C)C(=O)Cl
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NC1c2cc3nonc3cc2OC(C)(C)C1O
Temperature: 25 °C
Yield: 42 %

Procedure:
To a mixture of 200 mg (0.85 m mol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole, 130 μl (0.935 m mol) of triethyl amine and 20 ml of dichloromethane were added 98 μl (0.935 m mol) of isobutyryl chloride with stirring at the room temperature, followed by further stirring for four hours. After the completion of the reaction, the mixture was washed thrice with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was recrystallized from ethanol to obtain 109 mg (yield: 42%) of the pure intended compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]([C:9]1[CH:10]=[CH:11][C:12]([O:19][C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=2)=[C:13]([S:15](Cl)(=[O:17])=[O:16])[CH:14]=1)#[N:8]>C(Cl)Cl>[CH3:26][C:24]1[CH:25]=[C:20]([CH:21]=[C:22]([CH3:27])[CH:23]=1)[O:19][C:12]1[CH:11]=[CH:10][C:9]([C:7]#[N:8])=[CH:14][C:13]=1[S:15]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)(=[O:17])=[O:16]
Reactant: C1CNCCN1
Reactant: Cc1cc(C)cc(Oc2ccc(C#N)cc2S(=O)(=O)Cl)c1
Solvent: ClCCl
Product: Cc1cc(C)cc(Oc2ccc(C#N)cc2S(=O)(=O)N2CCNCC2)c1
Reaction time: 74 h
Yield: 58.5 %

Procedure:
To a solution of piperazine (16.144 g, 186.4 mmol) in CH2Cl2 (80 mL) stirred in an ice-brine bath was added dropwise of a solution of compound 23 (3.009 g, 9.35 mmol) in CH2Cl2 (270 mL) over the course of two days. The reaction was then stirred for 74 hrs, whereupon the starting material was consumed (TLC, 5% MeOH in CH2Cl2). The reaction mixture was partitioned between CH2Cl2 and water. The organic layer was then washed with saturated sodium chloride solution and dried over anhydrous MgSO4. The organic layer was then concentrated in vacuo, redissolved in a minimal amount of CH2Cl2, and chromatographed over normal phase silica (MeOH/CH2Cl2). The fractions containing the desired product were combined and concentrated in vacuo to yield an light yellow oil. The oil was then triturated with CH2Cl2/diisopropyl ether and vacuum filtered to afford compound 24 as a white powder (2.032 g, 58.5% yield, 95.5% HPLC purity). 1H NMR (500 MHz, DMSO-d6): δ 8.21 (d, J=2 Hz, 1H), 8.03 (dd, J1=9 Hz, J2=2 Hz, 1H), 7.01 (m, 1H), 6.96 (d, J=11 Hz, 1H), 6.80 (d, J=9 Hz, 2H), 3.19 (m, 2H), 3.11 (m, 2H), 2.70 (m, 2H), 2.46 (m, 2H), 2.30 (s, 1H), 2.27 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[C:11](F)=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:22])([F:21])[F:20])[C:16]([C:23]([O:25]CC)=[O:24])=[CH:15][C:14]=2[CH:28]=1>>[Cl:9][C:10]1[C:11]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:22])([F:20])[F:21])[C:16]([C:23]([OH:25])=[O:24])=[CH:15][C:14]=2[CH:28]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc(Cl)cc3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 4-chlorophenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 205.4-206.5° C. 1H NMR (acetone-d6 /300 MHz) 7.93 (s, 1H), 7.75 (s, 1H), 7.50 (d, 2H, J=8.9 Hz), 7.19 (d, 2H, J=8.9 Hz), 6.69 (s, 1H), 5.87 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6 /282 MHz) -79.4 (d, J=7.2 Hz). FABLRMS m/z 403 (M-H). ESHRMS m/z 402.9773 (M-H, Calc'd 402.9752). Anal. Calc'd for C17H9Cl2F3O4 : C, 50.40; H, 2.24; Cl, 17.50. Found: C, 50.02; H, 1.98; Cl, 17.79.
Reaction SMILES: [C:1]1(/[C:7](/[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(Cl)Cl>[C:27]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]/[CH:8]=[C:7](\[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)/[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: OCCCCC/C=C(\c1ccccc1)c1cccnc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCCCCC/C=C(\c1ccccc1)c1cccnc1
Reaction time: 18 h
Yield: 86 %

Procedure:
(E)-7-Phenyl-7-(3-pyridyl)-6-hepten-1-ol (0.4 g, 1.5 mmoles) was dissolved in methylene chloride (10 ml) and pyridine (0.4 ml) and acetic anhydride (0.2 ml) were added to the solution. The mixture was allowed to stand at room temperature for 18 hours and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using ethyl acetate as the developing solvent to give 1-acetoxy-(E)-7-phenyl-7-(3-pyridyl)-6-heptene (0.4 g, 86%) (Compound I-19) as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH2:7][CH2:8][N:9]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:5])C.O[Li].O>C1COCC1.O>[CH2:19]([N:9]1[CH2:10][C:11]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[C:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)C1=C(c2ccc(Cl)cc2)CN(Cc2ccccc2)CC1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1=C(c2ccc(Cl)cc2)CN(Cc2ccccc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 0.555 g (1.26 mmol) 1-benzyl-5-(4-chloro-phenyl)-1,2,3,6-tetrahydro-pyridine-4-carboxylic acid ethyl ester and 261 mg (6.2 mmol) LiOH.H2O in 15 mL THF and 5 mL water was stirred at room temperature over night. The mixture was evaporated to dryness, taken up in ethyl acetate, acidified with HCl to pH=1 and extracted with ethyl acetate. The combined organic layers were washed with water, evaporated to dryness and the residue was subjected to preparative HPLC chromatography on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid to yield after evaporation of the product containing fractions 0.254 g (50%) of the title compound as white solid. MS (m/e): 328.2 [(M+H)+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[C:21]1([CH:27]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30](=[O:37])[C:29]2=[O:38])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1.ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:30]2([OH:37])[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:28]([CH:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:29]2=[O:38])=[C:11]([OH:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(OCc2ccccc2)c1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1ccc(OCc2ccccc2)cc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
To a stirred solution of 3-(benzyloxy)phenol (8.7 g, 43.5 mmol) in tetrahydrofuran (100 mL) was added iso-propylmagnesium chloride (22.7 mL, 2 M tetrahydrofuran solution, 45.4 mmol) slowly at 0° C. The mixture was allowed to stir at 0° C. for 30 min, and concentrated in vacuo to dryness. Dichloromethane (100 mL) was added, followed by the addition of a solution of 1-(diphenylmethyl)-1H-indole-2,3-dione (12.4 g, 39.5 mmol) in dichloromethane (50 mL) at 0° C. The mixture was stirred at ambient temperature for 16 h, and quenched with saturated ammonium chloride solution. The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The obtained solid was recrystallized from ethyl acetate/hexanes to afford 3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one (19.60 g, 97%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.49-7.43 (m, 1H), 7.42-7.25 (m, 13H), 7.23-7.17 (m, 2H), 7.12-7.04 (m, 2H), 6.91 (s, 1H), 6.72-6.62 (m, 2H), 6.51-6.44 (m, 1H), 6.39 (dd, J=8.6, 2.4 Hz, 1H), 4.99 (s, 2H); MS (ES+) m/z 536.3 (M+23).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([CH:14]=O)=[CH:12][N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:23]O.C([O-])(=O)C.[Na+].P(Cl)(Cl)(Cl)=O>CN(C)C=O>[N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]#[N:23])=[CH:12][N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Stir 5 g of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxaldehyde together with 1.29 of hydroxylamine hydrochloride and 1.52 g of anhydrous sodium acetate in 15 ml of dimethylformamide for 1.5 hours at room temperature. Then add 2.85 g of phosphorus oxychloride dropwise to the resulting reaction mixture, the temperature of which rises to 40° C. Stir for 1 hour and then confirm that the reaction is complete by a thin layer chromatograph. Allow the solution to stand overnight and then pour onto 90 ml of ice water. Stir for 30 minutes at room temperature and then for 30 minutes at 40° C. Draw off the formed precipitate by vacuum filtration, wash the precipitate well with water and dry to obtain a 98% yield of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carbonitrile [m.p. 190° to 192° C].
Reaction SMILES: [F:1][C:2]([F:28])([C:13]1N2N=C(C3C=NN(C)C=3)C=CC2=[N:15][N:14]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.C([OH:31])C.O>>[F:1][C:2]([F:28])([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2)[C:13]([NH:14][NH2:15])=[O:31]
Reactant: Cn1cc(-c2ccc3nnc(C(F)(F)c4ccc5ncccc5c4)n3n2)cn1
Reactant: CCO
Solvent: O
Product: NNC(=O)C(F)(F)c1ccc2ncccc2c1

Procedure:
Form I of the compound of formula (I) (0.5 g, as prepared in Example 1) is heated at 60° C. in acetone/water mixture (50/50, vol/vol; 12 mL) for 1 hour. The solids are filtered and dried at 50° C. to provide 0.48 g of Form III.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:28][P:29](=[O:36])([O:33]CC)[O:30]CC)[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:17][CH2:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:28][P:29](=[O:30])([OH:33])[OH:36])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:22]2[N:23]=[CH:24][CH:25]=[CH:26][N:27]=2)[CH2:17][CH2:16]3)(=[O:10])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOP(=O)(CN(c1ccc2c(c1)CCN2c1ncccn1)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Solvent: ClCCl
Solvent: CO
Product: O=P(O)(O)CN(c1ccc2c(c1)CCN2c1ncccn1)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Reaction time: 1 h

Procedure:
70 mg diethyl {[(3,5-dichloro-phenylsulphonyl)-(1-pyrimidin-2-yl-2,3-dihydro-1H-indol-5-yl)-amino]-methyl}-phosphonate are dissolved in 3 ml dichloromethane. Under argon 200 μl trimethylsilylbromide are added thereto and the mixture is refluxed for 2 hours. After cooling to ambient temperature 1 ml of methanol is added and the mixture is stirred for a further 1 hour. Then the solvents are eliminated in vacuo. The residue is taken up in 3 ml of methanol, stirred for 10 minutes and the solvent is eliminated in vacuo. The residue thus obtained is extracted from dichloromethane with 1% methanol. The solid is suction filtered and dried.
Reaction SMILES: Cl[CH:2](P(=O)(OCC)OCC)[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[F:18][C:19]1[C:20]([CH:33]=O)=[CH:21][C:22]2[C:23]([CH3:32])([CH3:31])[CH2:24][CH2:25][C:26]([CH3:30])([CH3:29])[C:27]=2[CH:28]=1>>[F:18][C:19]1[C:20]([C:33]#[C:2][C:3]2[CH:4]=[CH:5][C:6]([CH3:9])=[CH:7][CH:8]=2)=[CH:21][C:22]2[C:23]([CH3:32])([CH3:31])[CH2:24][CH2:25][C:26]([CH3:29])([CH3:30])[C:27]=2[CH:28]=1
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)c(F)cc21
Reactant: CCOP(=O)(OCC)C(Cl)c1ccc(C)cc1
Product: Cc1ccc(C#Cc2cc3c(cc2F)C(C)(C)CCC3(C)C)cc1

Procedure:
Using a process similar to that described in Example 13, 27.7 g (0.1 mole) of diethyl 1-chloro-1-(4-tolyl)-methylphosphonate, 23.4 g (0.1 mole) of 3-fluoro-2-formyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene and 22.5 g (0.2 mole) of potassium tert.-butylate were reacted for 1 hour to give the title compound. Recrystallization from isopropanol gave 16.4 g (51%) of product of melting point 60°-61° C.