Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C([C@@H]([C@H](C(OCC)=O)O)O)(OCC)=[O:3].[CH3:16][C:17]1[C:18]([CH2:29][S:30][C:31]2[NH:35][C:34]3[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=3[N:32]=2)=[N:19][CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]([F:28])([F:27])[F:26].C(N(CC)C(C)C)(C)C.[O-]O.C1(C(C)C)C=CC=CC=1>C1(C)C=CC=CC=1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:16][C:17]1[C:18]([CH2:29][S:30]([C:31]2[NH:32][C:33]3[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=3[N:35]=2)=[O:3])=[N:19][CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]([F:27])([F:26])[F:28]
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [O-]O
Solvent: O
Solvent: CC(C)c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Temperature: 50 °C
Reaction time: 1 h
Yield: 38.4 %

Procedure:
For example, in Example 22 of this publication, it is described that a mixture, which was obtained by adding water (3.6 mmol), (+)-diethyl L-tartrate (15.0 mmol) and titanium(IV) isopropoxide (6.0 mmol) to a solution of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzimidazole (6.0 mmol) in toluene, stirring the resulting mixture at 50° C. for 60 min, cooling the reaction mixture to room temperature, adding N,N-diisopropylethylamine (6.0 mmol) and cumene hydroperoxide (6.0 mmol) and stirring the mixture at room temperature for 16 hr, consisted of 13% of sulfide, 8% of sulfone and 76% of sulfoxide as determined by achiral HPLC, that post-treatments of purification by flash chromatography and the like gave (+)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole (0.85 g) showing 46%ee enantiomer excess, and that, by further purification, 0.31 g (14%) of the objective substance having an optical purity of 99.6%ee was ultimately obtained as an oily substance.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([Br:20])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[O:22]=[C:23]1[CH2:28][O:27][C:26]2[CH:29]=[CH:30][C:31]([CH:33]=O)=[N:32][C:25]=2[NH:24]1.C([BH3-])#N.[Na+]>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]2[O:13][CH2:12][C:11](=[O:21])[N:10]([CH2:9][CH2:8][N:5]3[CH2:4][CH2:3][CH:2]([NH:1][CH2:33][C:31]4[CH:30]=[CH:29][C:26]5[O:27][CH2:28][C:23](=[O:22])[NH:24][C:25]=5[N:32]=4)[CH2:7][CH2:6]3)[C:15]=2[CH:16]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: NC1CCN(CCN2C(=O)COc3ccc(Br)cc32)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C1COc2ccc(CNC3CCN(CCN4C(=O)COc5ccc(Br)cc54)CC3)nc2N1
Yield: 22.1 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-bromo-2H-1,4-benzoxazin-3(4H)-one (Intermediate 65) (0.57 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (120 mg, 0.67 mmol) and sodium cyanoborohydride (72 mg, 1.14 mmol) were reacted as described under Example 21 to give 65 mg (22%) product as a solid.
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11]O)=[CH:10][C:4]=2[O:3]1.O=S(Cl)[Cl:16].O>CC(OC)(C)C.CN(C1C=CN=CC=1)C>[Cl:16][CH2:11][C:9]1[CH:8]=[CH:7][C:5]2[O:6][C:2]([F:13])([F:1])[O:3][C:4]=2[CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc2c(c1)OC(F)(F)O2
Agent: CN(C)c1ccncc1
Solvent: COC(C)(C)C
Solvent: O
Product: FC1(F)Oc2ccc(CCl)cc2O1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
(2,2-difluoro-1,3-benzodioxol-5-yl)-methanol (1.0 eq) was dissolved in MTBE (5 vol). A catalytic amount of 4-(N,N-dimethyl)aminopyridine (DMAP) (1 mol %) was added and SOCl2 (1.2 eq) was added via addition funnel. The SOCl2 was added at a rate to maintain the temperature in the reactor at 15-25° C. The temperature was increased to 30° C. for 1 h, and then was cooled to 20° C. Water (4 vol) was added via addition funnel while maintaining the temperature at less than 30° C. After stirring for an additional 30 min, the layers were allowed to separate. The organic layer was stirred and 10% (w/v) aq NaOH (4.4 vol) was added. After stirring for 15 to 20 min, the layers were allowed to separate. The organic phase was then dried (Na2SO4), filtered, and concentrated to afford crude 5-chloromethyl-2,2-difluoro-1,3-benzodioxole that was used directly in the next step.
Reaction SMILES: [CH2:1]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:16]([C:18]1([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[O:20][CH2:19]1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].ClCCCl>C(OCC)C>[CH3:24][C:21]1([CH3:25])[O:20][CH2:19][C:18]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH2:16][NH:13][C:12]2[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][CH:14]=2)[CH2:23][O:22]1
Reactant: CCCCCCCCc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)NC1(C=O)COC(C)(C)OC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOCC
Product: CCCCCCCCc1ccc(NCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1
Yield: 71.3 %

Procedure:
To a mixture of 4-n-octylaniline (0.21 g; 1 mmol), tert-butyl 5-formyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (Ooii et al, J. Org. Chem., 2004, 69, 7765; 0.26 g; 1 mmol) and NaBH(OAc)3 (0.3 g; 1.4 mmol) in 1,2-dichloroethane (3.5 ml) acetic acid (AcOH)(0.06 ml; 1 mmol) was added at room temperature with stirring under N2. After stirring for 2 h, the mixture was diluted to 20 ml with diethyl ether (Et2O), washed with 1.M NaOH (2×5 ml), brine and dried over anhydrous MgSC4 and filtered. The filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in hexane (5 ml) and kept in the freezer (−18° C.) overnight. The crystals formed were filtered off, washed with small volume of hexane and dried to give pure title compound (0.32 g; 71%), as colourless crystals. 1H-NMR (CDCl3) 0.86 (tr, 2H, J=6.95 Hz); 1.26 (m, 10H, 1.42, (s, 3H); 1.43 (s, 9H); 1.45 (s, 3H); 1.5 (m, 2H); 2.46 (tr, 2H, J=7.9 Hz); 3.44 (5, 2H); 3.8 (d, 2H, J=11.9 Hz); 3.85 (broad s, 1H); 4.01 (d, 2H, J=11.9); 4.84 (broad s, 1H); 6.58 (d, 2H, J=8.4 Hz); 6.96 (d, 2H, J=8.4 Hz).
Reaction SMILES: [N+:1]([CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[O-])([O-:3])=[O:2].[Na+].C(OC(=O)C)(=O)C.C(N(CC)CC)C>O1CCCC1>[N+:1](/[CH:4]=[CH:5]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])CC([O-])c1ccc(Oc2ccccc2)cc1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])/C=C/c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 139.5 %

Procedure:
A solution of sodium 2-nitro-1-(4-phenoxy-phenyl)ethanolate (1.17 g, 4.16 mmol) described in Manufacturing Example 17-1-1, acetic anhydride (510 mg, 4.99 mmol) and triethylamine (696 μL, 4.99 mmol) in anhydrous tetrahydrofuran (20 mL) was stirred overnight under nitrogen atmosphere at room temperature. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure to obtain the title compound (1.4 g, 70%, purity: ca. 50%) as a crude product.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:22])[CH2:20][NH2:21])=[CH:15][CH:14]=2)=[CH:9]1.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>>[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH2:22][C:24]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:25])[CH2:20][NH2:21])=[CH:15][CH:14]=2)=[CH:9]1
Reactant: CC(CN)c1ccc(-c2ccsc2)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NCC(CC(=O)Oc1ccccc1)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared from 2-(4-(3-thienyl)phenyl)propyl amine trifluoroacetate (prepared in example 1) and phenyl chloroformate in a manner analogous to the procedure described in Example 1.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[CH2:19]([NH2:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>O>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:26][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:6]=1)[CH:2]=[CH2:3]
Reactant: CCCCCCCN
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Solvent: O
Product: C=CCNc1nc(NCCCCCCC)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
A mixture of 200 mg (0.76 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 1.55 g (13.49 mmol) of heptylamine was stirred at room temperature for 2 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate, washing brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 228 mg (87.8%) of the title compound.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH2:10][NH:11][C:12]2[C:16]([CH2:17][OH:18])=[CH:15][NH:14][N:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[C:25]1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>CO>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH2:10][NH:11][C:12]2[C:16]([CH2:17][O:18][CH3:25])=[CH:15][NH:14][N:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(CNc2n[nH]cc2CO)cc1OC1CCCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCc1c[nH]nc1NCc1ccc(OC)c(OC2CCCC2)c1

Procedure:
A solution of 3-(3-cyclopentyloxy-4-methoxybenzylamino)-4-hydroxymethylpyrazole (1.0 g, 3.15 mmol) and p-toluenesulfonic acid monohydrate (0.2 g, 1.0 mmol) in methanol (100 mL) was kept at room temperature for 10 min. The reaction mixture was neutralized with 1 N aqueous sodium hydroxide and evaporated under reduced pressure at room temperature. The residue-was partitioned between water (50 mL) and ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (10 mL). The combined ethyl acetate layers were washed with water and evaporated under reduced pressure. The residue was taken up in a small volume of methylene chloride and applied to a 4 mm silica gel disk on a Chromatotron. Elution with 525 mL of methylene chloride and 275 mL of 1% methanol/methylene chloride removed some impure material. Continued elution with 75 mL of 1% methanol/methylene chloride afforded 380 mg (36%) of pure 3-(3-cyclopentyloxy-4-methoxybenzylamino)-4-methyoxymethylpurazole, mp. 112-115°.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C@H:12]3[CH2:16][C@:5]([C:17]([N:19]4[CH2:24][CH2:23][CH:22]([CH2:25][C:26]5[C:27](F)=[N:28][CH:29]=[CH:30][CH:31]=5)[CH2:21][CH2:20]4)=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.[F-].[K+].[CH3:35][O-:36].[Na+]>CO>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C@H:12]3[CH2:16][C@:5]([C:17]([N:19]4[CH2:24][CH2:23][CH:22]([CH2:25][C:26]5[C:27]([O:36][CH3:35])=[N:28][CH:29]=[CH:30][CH:31]=5)[CH2:21][CH2:20]4)=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: C[O-]
Reactant: O=C(N1CCC(Cc2cccnc2F)CC1)[C@@]12C[C@@H](c3ccccc31)c1ccc(Cl)cc12
Agent: [F-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: COc1ncccc1CC1CCN(C(=O)[C@@]23C[C@@H](c4ccccc42)c2ccc(Cl)cc23)CC1
Temperature: 25 °C
Yield: 68 %

Procedure:
To a solution of 1-((9S,10S)-2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylcarbonyl)-4-(2-fluoro-3-pyridylmethyl)piperidine, (2.60 g, 5.8 mmol), prepared as described in Example 55a, in methanol (25 mL) was added potassium fluoride (4.15 g, 71.4 mmol) which caused a slight exotherm (~35° C.). Sodium methoxide solution in methanol (4.4 mL of a 25 wt % solution) was added which caused another exotherm (~50° C.) and thinned the suspension. This suspension was heated to reflux for 6 h. Additional potassium fluoride (4.15 g, 71.4 mmol) was added and the suspension was refluxed for 18 h. Additional sodium methoxide solution (1.0 mL) was added and the suspension was refluxed for 5 h. The mixture was cooled to room temperature, partitioned between basic brine and dichloromethane. The organic extract was separated and the aqueous was extracted with dichloromethane (2X). The dichloromethane extracts were combined, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The crude foam was purified by flash chromatography on silica (eluant: 15% acetone/hexanes) to give the title compound as a white solid (1.82 g, 3.95 mmol, 68%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[NH:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.[OH-].[Na+].C1COCC1.Cl>CO>[NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[NH:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(N)c(NC(=O)c2ccc(OC)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C(=O)Nc2cc(C(=O)O)ccc2N)cc1
Yield: 97.2 %

Procedure:
A suspension of 107 (400 mg, 1.33 mmol) and 1M NaOH (2.7 ml, 2.66 mmol) in 1:1 THF:MeOH (6 ml) was heated at 50° C. for 16 h. HCl 1M was added to reach pH=4 and the solid was filtered to give 370 mg (97%) of compound 108 as a white solid. 1H NMR: (DMSO) δ (ppm): 9.52 (s, 1H), 7.96 (d, J=8.8 Hz, 2H), 7.71 (d, J=2.0 Hz, 1H), 7.54 (dd, J=8.4, 2.0 Hz, 1H), 7.02 (d, J=9.0 Hz, 2H), 6.74 (d, J=8.4 Hz, 1H), 5.69 (s, 2H), 3.83 (s, 3H). MS: (calc.) 361.1; (obt.) 362.3 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](Cl)[CH:20]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:16])([F:18])[F:17])[N:12]=[C:11]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:30]4[CH:29]=[N:28][C:27]([NH2:26])=[CH:32][CH:31]=4)[CH:20]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2ccnc(Cl)c2)n1
Product: Nc1ccc(-c2cc(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)ccn2)cn1

Procedure:
The title compound was prepared from 4-(3,4-dichloro-phenyl)-2-(2-chloro-pyridin-4-yl)-6-trifluoromethyl-pyrimidine (example E.38) (0.20 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a light brown solid (0.15 g, 63%). MS (ISP) 462.1 [(M+H)+]; mp 224.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([C:7]([OH:10])=[CH:8][CH:9]=1)[CH:5]=[O:6].Br[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:4]([CH:5]=[O:6])[C:3]=1[O:11][CH3:12]
Reactant: CCOC(=O)CCCCBr
Reactant: COc1c(Cl)ccc(O)c1C=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CCCCOc1ccc(Cl)c(OC)c1C=O
Reaction time: 17 h

Procedure:
3-Chloro-6-hydroxy-2-methoxybenzaldehyde (1.9 g, 0.0102 M), ethyl 5-bromopentanoate (2.13 g. 0.0102 M), anhydrous potassium carbonate (1.55 g), sodium iodide (56 mg), and 95% ethanol (25 ml) were refluxed with stirring (17 hr). The cooled reaction mixture was filtered and the solid washed well with ethanol. The filtrate was evaporated to dryness and the residue partitioned between ether and water. The organic layer was separated and washed with 2 N sodium hydroxide solution, water, dried (magnesium sulphate) and evaporated to give ethyl 5-(4-chloro-2-formyl-3-methoxyphenoxy)pentanoate as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11][C:6]2(OCC[O:7]2)[CH2:5][CH2:4]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[CH3:1][O:2][C:3]1([C:13]([F:14])([F:15])[F:16])[CH2:4][CH2:5][C:6](=[O:7])[CH2:11][CH2:12]1
Reactant: COC1(C(F)(F)F)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: COC1(C(F)(F)F)CCC(=O)CC1

Procedure:
11.80 g (49.12 mmol) of 8-methoxy-8-(trifluoromethyl)-1,4-dioxaspiro[4.5]decane (Example 9A) were dissolved in 236 ml of acetone and 118 ml of water, 1.50 g (7.86 mmol) of 4-toluenesulphonic acid monohydrate were added and the mixture was heated at reflux overnight. The mixture was then poured into 1.2 l of water and the product was extracted with diethyl ether. The organic phase was washed with water, dried over sodium sulphate and concentrated under reduced pressure. The resulting residue was distilled under reduced pressure (boiling point: 106-110° C. at 40 mbar). This gave 6.86 g (71% of theory) of the title compound as a yellowish oil.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:5]2[N:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][N:4]2[N:3]=1.C(Cl)(=O)C(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[NH2:26][CH2:27][C:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1.Cl>O1CCCC1.O.CN(C)C=O>[NH2:33][C:28]1([CH2:27][NH:26][C:10]([C:8]2[CH:7]=[N:6][C:5]3[N:4]([N:3]=[C:2]([CH3:1])[CH:13]=3)[CH:9]=2)=[O:12])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cc1cc2ncc(C(=O)O)cn2n1
Reactant: NCC1(N)CCCC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2ncc(C(=O)NCC3(N)CCCC3)cn2n1
Reaction time: 1 h
Yield: 11.9 %

Procedure:
2-Methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.31 g) was suspended in tetrahydrofuran (7 ml), and N,N-dimethylformamide (0.04 ml) was added thereto. A solution of oxalyl chloride (200 μl) in tetrahydrofuran (0.8 ml) was added dropwise thereto with ice cooling, and the mixture was stirred for 1 hour at the same temperature and then stirred for 2 hours at room temperature. Potassium carbonate (0.54 g) was added thereto at −60° C. or less, and then a solution of 1-(aminomethyl)cyclopentylamine (0.22 g) in tetrahydrofuran (0.8 ml) was added dropwise thereto. The mixture was stirred for 30 minutes at −60° C. or less and then stirred for 22 hours at room temperature. Water (6 ml) was added thereto on an ice bath, and the reaction mixture was adjusted to pH 2 by 6 N hydrochloric acid. The reaction mixture was washed with chloroform, and the aqueous phase was adjusted to pH 12 by 5 N sodium hydroxide solution and extracted with chloroform. The resulting product was washed with a saturated saline solution and then dried over sodium sulfate anhydrous. The product was concentrated under reduced pressure to give the title compound (57 mg, Y.:12%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][CH:9]([CH:17]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(CC)CC)C>ClCCl>[I:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][CH2:18][CH:17]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH:9]([CH2:8][CH2:7][O:6][S:2]([CH3:1])(=[O:4])=[O:3])[C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[CH:25][CH:24]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(COC(CCc2ccc(I)cc2)C(CCO)C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(COC(CCc2ccc(I)cc2)C(CCOS(C)(=O)=O)C(=O)OC(C)(C)C)cc1
Yield: 100.5 %

Procedure:
Methanesulfonyl chloride (315 μL, 5.91 mmol) was added in one portion to a stirred solution of 1,1-dimethylethyl 2-(2-hydroxyethyl)-5-(4-iodophenyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)pentanoate (2.00 g, 3.70 mmol) and triethylamine (1.03 mL, 7.39 mmol) in dichloromethane (10 mL) at room temperature under nitrogen. After stirring at room temperature for 1 h the crude mixture was partitioned between saturated aqueous citric acid solution (40 mL) and dichloromethane (40 mL). The phases were separated and the organic layer was evaporated to give the title compound (2.3 g, 100%) as a yellow oil which was a mixture of diastereomers. LC/MS: 4.00 min; z/e 636, calcd (M+18) 636. 1H NMR (400 MHz: CDCl3): 7.60-7.20 (4H), 6.90-6.75 (4H), 4.60-4.20 (5H), 3.80 (3H), 2.95 (3H), 2.90-2.45 (3H), 2.10-1.70 (4H), 1.40 (9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][C:15](O)=O.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[CH3:39][O:40][C:41]1[CH:42]=[CH:43][C:44]2[O:49][CH2:48][CH:47]([CH2:50][NH2:51])[O:46][C:45]=2[CH:52]=1>CN(C=O)C>[CH3:39][O:40][C:41]1[CH:42]=[CH:43][C:44]2[O:49][CH2:48][CH:47]([CH2:50][NH:51][CH2:15][CH2:14][CH2:13][CH2:12][C:6]3[C:5]4[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=4)[NH:8][CH:7]=3)[O:46][C:45]=2[CH:52]=1
Reactant: COc1ccc2c(c1)OC(CN)CO2
Reactant: COc1ccc2[nH]cc(CCCC(=O)O)c2c1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OC(CNCCCCc1c[nH]c3ccc(OC)cc13)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
5-Methoxyindole-3-butyric acid (1.0 g, 4.3 mmole), 1-hydroxybenzotriazole hydrate (0.7 g, 5.2 mmole) and 1,3-diisopropylcarbodiimide (1.6 ml, 10.3 mmole) were combined in 150 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 7-methoxy-2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.0 g, 4.3 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and replaced with dichloromethane. The mixture was then washed with H2O. The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as eluant. Evaporation of product-containing fractions gave 1.3 g (74%) of the desired product, (7-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-4-(5-methoxy-1H-indol-3-as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[C:6]=2[CH:17]=1.BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[C:6]=2[CH:17]=1
Reactant: Cc1ccc2c(c1)C(=O)c1ccccc1CC2
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc2ccc3ccccc3c(=O)c2c1
Yield: 74.1 %

Procedure:
The ketone from Step B (30.25 g) and N-bromosuccinimide (29.1 g) were refluxed in carbon tetrachloride (300 ml) for 5 hrs. The solution was cooled, filtered and evaporated and the residue dissolved in dimethylformamide (100 ml) and 1,5-diazabicyclo[4.3.0]non-5-ene (22 g) added. The solution was heated to 80° for 20 mins, then poured into water (300 ml) and extracted with ether (3×300 ml). The extract was washed with dilute aqueous hydrochloric acid and water, then dried and evaporated. Crystallisation from acetone/hexane gave pure 3-methyl-5H-dibenzo[a,d]cyclohepten-5-one (22.2 g). m.p. 81°-83° C.