Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:12][C:13]([C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)=[O:14].C(N(CC)CC)C>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][N:9]([CH3:10])[CH2:12][C:13]([C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)=[O:14]
Reactant: O=C(CBr)c1ccc2ccccc2c1
Reactant: CNCc1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CN(CC(=O)c1ccc2ccccc2c1)Cc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 109.9 %

Procedure:
To a solution of Compound 14 (23.1 g, 115.5 mmol) in methylene chloride (500 mL) was added α-bromo-2′-acetonapthone (27.9 g, 110.0 mmol) and the resulting mixture was stirred at 0° C. for 1 h prior to the addition of triethylamine (15.3 mL, 47.4 mmol). The reaction mixture was stirred at 0° C. for 2 h. The resulting mixture was diluted with water (200 mL) and the aqueous phase was extracted with additional methylene chloride (2×200 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated to afford Compound 15 (44.5 g) as a light yellow oil, which was used in the next step without further purification: 1H NMR (CDCl3, 500 MHz) δ 8.49 (s, 1H), 8.01 (dd, J=8.8, 1.8 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.90-7.84 (m, 2H), 7.62-7.52 (m, 3H), 7.40 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.19 (t, J=7.7 Hz, 1H), 3.91 (s, 2H), 3.68 (s, 2H), 2.40 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:14](=[O:16])[CH3:15])[CH:8]=[C:9]([OH:13])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][CH2:19][CH2:20][O:21][CH3:22]>>[C:1]([C:5]1[CH:6]=[C:7]([C:14](=[O:16])[CH3:15])[CH:8]=[C:9]([O:13][CH2:18][CH2:19][CH2:20][O:21][CH3:22])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCCBr
Reactant: COc1c(O)cc(C(C)=O)cc1C(C)(C)C
Product: COCCCOc1cc(C(C)=O)cc(C(C)(C)C)c1OC
Yield: 56.6 %

Procedure:
1-(3-tert-Butyl-5-hydroxy-4-methoxyphenyl)ethanone (O3.070; 2.00 g) and 1-bromo-3-methoxypropane (1.65 g) were converted, worked up and purified analogously to O2.110. 1.50 g of the title compound were obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:15]([NH:17][C:18]1[CH:19]=[N:20][N:21]([CH3:24])[C:22]=1[NH2:23])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C.[C:32]([O:36][C:37]([NH:39][CH2:40][CH2:41][C:42](ON1C(=O)CCC1=O)=[O:43])=[O:38])([CH3:35])([CH3:34])[CH3:33]>C(Cl)(Cl)Cl>[NH2:23][C:22]1[N:21]([CH3:24])[N:20]=[CH:19][C:18]=1[NH:17][C:15](=[O:16])[C@@H:2]([NH:1][C:42](=[O:43])[CH2:41][CH2:40][NH:39][C:37]([O:36][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:38])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: Cn1ncc(NC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C)c1N
Reactant: CC(C)(C)OC(=O)NCCC(=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cn1ncc(NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CCNC(=O)OC(C)(C)C)c1N
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.3 %

Procedure:
To a solution of tert-butyl (5S)-5-amino-6-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-6-oxohexylcarbamate (1.60 g) and triethylamine (0.47 g) in chloroform (100 ml) was added N-[3-(tert-butoxycarbonylamino)propionyloxy]succinimide (1.34 g). The mixture was stirred at room temperature for 15 hours. The mixture was washed with saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a crude product of tert-butyl (5S)-6-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-5-{[3-(tert-butoxycarbonylamino)propionyl]amino}-6-oxohexylcarbamate (2.09 g) as an oil. The crude product was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][C:10]([P:16]([OH:19])([OH:18])=[O:17])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH3:7].[OH-].[Na+:21].CC(C)=O>C(#N)C>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][C:10]([P:16]([O-:19])([OH:18])=[O:17])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH3:7].[Na+:21]
Reactant: CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CC#N
Product: CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O
Temperature: 25 °C
Yield: 65.5 %

Procedure:
A slurry of amorphous ibandronic acid (5 g) in acetonitrile (200 ml) was stirred at reflux temperature. Solid sodium hydroxide (0.63 g) was added, and the reaction mixture was stirred at reflux temperature for an additional 2 hours. Acetone (50 ml) was added dropwise. Then the reaction mixture was cooled to room temperature and stirred for 16 hours. The precipitate was isolated by vacuum filtration, washed with acetone (50 ml), and dried in a vacuum oven at 50° C. for 22 hours to obtain 3.5 g of amorphous ibandronate sodium.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[CH:3][C:2]=1[C:10]([OH:12])=O.ClC(N(C)C)=C(C)C.CCN(C(C)C)C(C)C.[NH:30]1[C:38]2[C:33](=[C:34]([C:39]3[CH:40]=[C:41]([NH2:54])[C:42]4[C:46]([CH:47]=3)=[N:45][N:44](C3CCCCO3)[CH:43]=4)[CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31]1.CC1C=CC(S(O)(=O)=O)=CC=1.N>C1COCC1.CO>[NH:30]1[C:38]2[C:33](=[C:34]([C:39]3[CH:47]=[C:46]4[C:42]([CH:43]=[N:44][NH:45]4)=[C:41]([NH:54][C:10]([C:2]4[CH:3]=[C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][N:5]5[N:1]=4)=[O:12])[CH:40]=3)[CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Reactant: O=C(O)c1cc2ccccn2n1
Agent: CC(C)=C(Cl)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cc2ccccn2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Pyrazolo[1,5-a]pyridine-2-carboxylic acid (27 mg, 0.166 mmol) was treated with anhydrous THF (2 ml) and then 1-chloro-N,N, 2-trimethylpropenylamine (0.026 ml, 0.20 mmol). The reaction was stirred at room temperature under nitrogen for 2 hrs. The reaction was then treated with anhydrous DIPEA (0.131 ml, 0.753 mmol) and 2 ml of solution of 6-(1H-indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (750 mg, 2.26 mmol) in THF (30 ml). The reaction was then stirred at room temperature under nitrogen for 69 hrs. The solvent was blown-off under a stream of nitrogen, dissolved in methanol (3 ml) and then solvent removed under reduced pressure. The crude reaction mixture was dissolved in methanol (5 ml), treated with Macroporous Tosic Acid (4.45 mmol/g, 102 mg, 0.45 mmol), stirred at room temperature for 17 hrs and then treated with 0.88 ammonia (0.5 ml), stirred for 30 minutes and then filtered. The solvent was removed under reduced pressure and then the residue purified by Mass Directed Automated Preparative HPLC (Method B) to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:25]=[C:24]4[C:20]([CH:21]=[CH:22][NH:23]4)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:39]([O:41][C:42](=[O:46])[CH2:43][CH2:44]Br)[CH3:40]>CS(C)=O>[CH2:39]([O:41][C:42](=[O:46])[CH2:43][CH2:44][N:23]1[C:24]2[C:20](=[CH:19][CH:18]=[C:17]([CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([C:5]4[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=4[O:26][CH3:27])=[CH:10][CH:11]=3)[CH:25]=2)[CH:21]=[CH:22]1)[CH3:40]
Reactant: CCOC(=O)CCBr
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3cc[nH]c3c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ccc2ccc(COc3ccc(-c4cc(F)c(F)cc4OC)cc3)cc21
Temperature: 90 °C
Yield: 70.9 %

Procedure:
To 6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1H-indole (37 mg, 0.10 mmol, 1 eq.) was added dimethylformamide (1 mL), cesium carbonate (40 mg, 0.11 mmol, 1.1 eq.) and 3-bromo-propionic acid ethyl ester (0.014 mL, 0.11 mmol, 1.1 eq.). The reaction was stirred and heated at 90° C. for 17 hr. The reaction was diluted with dimethylsulfoxide, filtered, and purified by HPLC with a 50-100% acetonitrile in water gradient to yield 3-[6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-propionic acid ethyl ester as clear oil (33 mg, 73%). LC-MS (ES) calculated for C27H25F2NO4, 465.2; found m/z 466 [M+H]+.
Reaction SMILES: [N:1]1([CH2:8][C@H:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH:25]4[CH3:29])=[CH:16][CH:15]=3)[C:12](=O)[CH2:11][CH2:10]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:40]2)=CC=1.C1(C)C=CC=CC=1.O>C(Cl)(Cl)Cl>[N:1]1([CH2:8][C@H:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH:25]4[CH3:29])=[CH:16][CH:15]=3)[C:12](=[S:40])[CH2:11][CH2:10]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1CCCN1CCCOc1ccc(N2C(=O)CC[C@H]2CN2CCCCCC2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC1CCCN1CCCOc1ccc(N2C(=S)CC[C@H]2CN2CCCCCC2)cc1
Yield: 35 %

Procedure:
(5S)-5-(azepan-1-ylmethyl)-1-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}pyrrolidin-2-one 20 (0.1 g, 0.24 mmol, 1 eq) is dissolved in chloroform (5 ml) and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide a49 (Lawesson's reagent, 0.05 g, 0.12 mmol, 0.5 eq) is added. Toluene (5 ml) is added and the mixture is refluxed for 6 h. Water is then added, and after phase separation, the organic layer is dried over magnesium sulfate and concentrated to give 0.2 g of crude material. Purification by chromatography over silicagel (dichloromethane/methanol/ammonia 94/6/0.6) affords 0.05 g of pure (5S)-5-(azepan-1-ylmethyl)-1-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}pyrrolidine-2-thione 21.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C:10]([OH:12])=O)=O)(C)(C)C.[ClH:20].[CH3:21][NH:22][CH3:23].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[ClH:20].[NH2:8][C@@H:9]([CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C:10]([N:22]([CH3:23])[CH3:21])=[O:12]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccnc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@@H](N)Cc1cccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-2-tert-butoxycarbonylamino-3-pyridin-3-ylpropionic acid (500 mg, 1.88 mmol) in DMF (10 mL) was added dimethylamine hydrochloride (153 mg, 1.88 mmol), DIPEA (1.2 mL, 6.57 mmol) and TBTU (602 mg, 1.88 mol). The reaction mixture was stirred at rt for 16 h. The solvent was removed in vacuo and the residue dissolved in methanol (20 mL). To this was added 4M hydrochloric acid in dioxane (20 mL) and the reaction was stirred for 16 h at rt. The solvent was removed in vacuo and the residue was partitioned between water (100 mL) and ethyl acetate (2×100 mL). The aqueous layer was evaporated to dryness and the residue recrystallised from ethanol/ethoxyethanol (9:1), to give the title compound as a white solid. δH (CD3OD): 2.99 (3H, s), 3.06 (3H, s), 3.35-3.42 (1H, m), 3.45-3.53 (1H, m), 4.87-4.94 (1H, m), 8.04-8.10 (1H, m), 8.48-8.53 (1H, m), 8.84-8.90 (2H, m).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:10]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[C:11]([CH2:17]CO)[C:12]([O:14][CH2:15]C)=[O:13])[CH:7]=[CH:8][CH:9]=1>O.C(O)C.C1(C)C=CC=CC=1>[F:3][C:4]1[CH:5]=[C:6](/[C:10](=[C:11]2\[C:12](=[O:13])[O:14][CH2:15][CH2:17]\2)/[C:20]2[CH:21]=[CH:22][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:24][CH:25]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(CCO)=C(c1ccc(S(C)(=O)=O)cc1)c1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)c1ccc(/C(=C2\CCOC2=O)c2cccc(F)c2)cc1
Yield: 15.5 %

Procedure:
3.3 g of sodium hydroxide dissolved in 10 ml of water are added to a solution of 29.3 g of ethyl 3-(3-fluorophenyl)-3-(4-methanesulfonylphenyl)-2-(2-hydroxyethyl)-2-propenoate, prepared in Example 12, in 50 ml of ethanol and the mixture is refluxed for 2 hours. After evaporation to dryness, the residue is taken up with water, acidified with 1N hydrochloric acid and then extracted with dichloromethane. The organic phase is dried over magnesium sulfate and evaporated under vacuum to give an oily residue. The oil is solubilized in 150 ml of toluene, and 10 mg of paratoluenesulfonic acid are added. The mixture is refluxed and the water formed is removed with a Dean-Stark apparatus. After cooling, the mixture is washed with water, the organic phase is dried over magnesium sulfate and evaporated under vacuum and the residue is chromatographed on silica in t-butyl methyl ether to give 4 g of (Z)-3-[1-(3-fluorophenyl)-1-(4-methanesulfonylphenyl)methylidene]dihydrofuran-2-one (2nd product eluted) in the form of crystals melting at 153°-154° C.
Reaction SMILES: [H-].[Na+:2].[CH:3]([OH:6])([CH3:5])[CH3:4].[P:7]([Cl:11])(Cl)(Cl)=[S:8]>C1COCC1>[CH3:4][CH:3]([CH3:5])[O-:6].[Na+:2].[P:7]([Cl:11])([O:6][CH:3]([CH3:5])[CH3:4])([O:6][CH:3]([CH3:5])[CH3:4])=[S:8]
Reactant: CC(C)O
Reactant: S=P(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)OP(=S)(Cl)OC(C)C
Product: CC(C)[O-]
Temperature: -40 °C
Yield: 117.1 %

Procedure:
A solution of sodium isopropoxide in THF was prepared by the reaction of 45 g (1125 mmole) of 60% sodium hydride with 84 ml (1100 mmole) of isopropyl alcohol in 400 ml of THF. This solution was added, with mechanical stirring, to 83.4 g (490 mmole) of thiophosphorylchloride in 300 ml of THF and cooled to -40° C. internal. After the addition was complete the reaction mixture was slowly warmed to 25° C. When gas chromatography showed the reaction to be complete the THF was removed in vacuo and the product partitioned between hexanes and water. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo yielding 93 g of the title compound, an oil. nmr 1.4 d 12H, 4.9 m 2H.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[CH3:31][N:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([N:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH:42]=1.CCN(C(C)C)C(C)C>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[C:14]([N:50]1[CH2:51][CH2:52][N:47]([C:43]2[CH:44]=[CH:45][CH:46]=[C:41]([C:33]3[N:32]([CH3:31])[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[N:34]=3)[CH:42]=2)[CH2:48][CH2:49]1)=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCOCC1C(=O)O
Reactant: Cn1c(-c2cccc(N3CCNCC3)c2)nc2ccccc21
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cn1c(-c2cccc(N3CCN(C(=O)C4COCCN4C(=O)OC(C)(C)C)CC3)c2)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
To a solution of morpholine-3,4-dicarboxylic acid-4-tert-butyl ester (0.16 g, 0.71 mmol) in acetonitrile (8 mL) was added CDI (0.16 g, 0.71 mmol) and the resulting suspension was stirred at room temperature overnight. 1-Methyl-2-(3-piperazin-1-yl-phenyl)-1H-benzoimidazole dihydrochloride (0.20 g, 0.55 mmol) (obtained as described in method C) and DIPEA (0.19 mL, 1.10 mmol) were added and the resulting solution heated at 65° C. overnight. The reaction was then cooled to room temperature, the solvent removed, the crude product was dissolved with dichloromethane (15 mL) and washed with saturated NaHCO3 solution (2×3 mL) The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (eluent: gradient from cyclohexane to cyclohexane:EtOAc 2:1) to afford 0.11 g (40%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][CH:7]=1.C[CH2:10][N:11](CC)CC.[Si](C#N)(C)(C)C>CC#N.C(Cl)Cl>[F:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: [O-][n+]1cccc(F)c1
Agent: C[Si](C)(C)C#N
Solvent: ClCCl
Solvent: CC#N
Product: N#Cc1ncccc1F
Yield: 77.3 %

Procedure:
To a solution of 3-fluoropyridine 1-oxide (1.21 g, 10.7 mmol) in CH3CN (10 mL) was added Et3N (4.4 mL, 31.6 mmol) followed by TMSCN (4.3 mL, 32.2 mmol) and the reaction was stirred at reflux for 6.5 hours. The mixture was diluted with CH2Cl2 (100 mL) and washed with saturated aqueous NaHCO3 (50 mL). The aqueous layer was extracted with CH2Cl2 (3×40 mL) and the combined organic layers were dried (Na2SO4), filtered and concentrated to give a crude dark red oil. Purification of the crude material by column chromatography on silica gel (CH2Cl2/MeOH, 98:2) afforded the title compound as a yellow solid (1.01 g, 77%). 1H NMR (CDCl3): δ 7.58-7.67 (m, 2H), 8.54-8.57 (m, 1H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:23]=[CH:22][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[O:20][N:19]=[C:18]([CH3:21])[CH:17]=2)=[C:8]([CH:24]=[O:25])[CH:7]=1.[BH4-].[Na+]>CO.C(O)(=O)C.O>[O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:23]=[CH:22][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[O:20][N:19]=[C:18]([CH3:21])[CH:17]=2)=[C:8]([CH2:24][OH:25])[CH:7]=1
Reactant: Cc1cc(CCCCCOc2ccc(C3=NCCO3)cc2C=O)on1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(CCCCCOc2ccc(C3=NCCO3)cc2CO)on1
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a solution of 1.2 g of 5-{5-[4-(4,5-dihydro-2-oxazolyl)-2-formylphenoxy]pentyl}-3-methylisoxazole (Example 70) in 10 ml of methanol was added in portions 0.2 g of sodium borohydride. The mixture was stirred for one hour, then treated with a few drops of glacial acetic acid and diluted to 50 ml with water. The solid product was collected, washed with aqueous methanol and recrystallized from ethyl acetate to give 1.2 g of 5-{5-[4-(4,5-dihydro-2-oxazolyl)-2-hydroxymethylphenoxy]pentyl}-3-methylisoxazole, m.p. 140°-141° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.N1C=CC=CC=1.[C:17](Cl)(=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(Cl)Cl>[C:17]([CH:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:9])(=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCC(=O)Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCC(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (43.2 g, 300 mmol) and pyridine (47.5 g, 600 mmol) in 300 ml of CH2Cl2 was added hexanoyl chloride (40.4 g, 300 mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 1 hr then at room temperature for 1 hr. The solution was washed with 1N aqueous HCl (300 ml), water (300 ml) and dried over Na2SO4. After evaporation of solvent, 5-hexanoyl-2,2-dimethyl-1,3-dioxane-4,6-dione was obtained as a light pink oil (35.4 g, 62%).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[CH:11]([NH2:13])[CH2:10][CH2:9]2.S(Cl)([Cl:17])(=O)=O>C(O)(=O)C>[Cl:1][C:7]1[CH:6]=[C:5]([Cl:17])[C:4]([O:3][CH3:2])=[C:12]2[C:8]=1[CH2:9][CH2:10][CH:11]2[NH2:13]
Reactant: COc1cccc2c1C(N)CC2
Reactant: Cl
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: COc1c(Cl)cc(Cl)c2c1C(N)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 78334 %

Procedure:
Rac-7-methoxy-indan-1-ylamine hydrochloride (2.20 g, 0.011 mmol) was dissolved in acetic acid (100 mL). After cooling to 0° C. sulfuryl chloride (1.88 mL, 0.23 mmol) was slowly added and the reaction mixture was stirred for 16 h at ambient temperature. Then the solvent was evaporated and the residue was taken up in isopropanol. Thereby a precipitate formed which was isolated and dried on high vacuum to yield rac-4,6-dichloro-7-methoxy-indan-1-ylamine (2.0 g, 68%) as a white solid; MS: m/e=269.6 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:16][O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25]Br)[CH:20]=1>>[CH3:16][O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[NH:9][CH:8]=3)[CH2:3][CH2:2]2)[CH:20]=1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: COC(=O)c1cccc(CBr)c1
Product: COC(=O)c1cccc(CN2CCC(c3c[nH]c4ccccc34)CC2)c1
Yield: 79.2 %

Procedure:
This compound was prepared following the procedure described in example 1 (part D) starting with 0.2 g (1 mmol) of 3-piperidin-4-yl-1H-indole and 0.29 g (1.3 mmol) of 3-bromomethyl-benzoic acid methyl ester. After ionic exchange purification, 0.276 g (79% of yield) of 3-[4-(1H-indol-3-yl)-piperidin-1-ylmethyl]-benzoic acid methyl ester were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]#[N:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].C(Cl)(=O)C.[NH3:27]>C1(C)C=CC=CC=1.CO>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17](=[NH:27])[NH2:18])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:19]([F:20])([F:21])[F:22]
Reactant: N#CCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: N
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CC(=O)Cl
Product: Cl
Product: N=C(N)CCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.4 %

Procedure:
To a solution of 3-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)propanenitrile (20.0 g, 61.4 mmol) in toluene (30 mL) and methanol (30 mL) was added dropwise acetyl chloride (18.8 g, 239 mmol) over 5 min at 0° C. under N2. The reaction mixture was stirred at 25° C. for 8 h, then concentrated. It was dissolved with toluene (5 mL), cooled to 0° C. in an ice-bath, slowly mixed with ammonia (30.0 mL, 210 mmol), stirred at 25° C. overnight, filtered, washed with toluene/methanol (1/1) and concentrated. Purification via recrystallization with diethyl ether (50 mL) then afforded the title compound as a white solid (5.4 g, 25.7%).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C)C=O>[Si:27]([O:26][CH2:25][CH2:24][CH2:23][S:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:5]#[N:6])([C:30]([CH3:31])([CH3:32])[CH3:33])([CH3:29])[CH3:28]
Reactant: N#Cc1ccc(-c2ccccc2)c(S)c1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCSc1cc(C#N)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-mercapto-4-phenylbenzonitrile (0.44 g) in N,N-dimethylformamide (5.0 mL) was added potassium carbonate (0.43 g). Then (3-bromopropoxy)-tert-butyldimethylsilane (0.72 mL) was added, and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned between diethyl ether (55 mL) and water (10 mL). The organic layer was washed with water (10 mL×2) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethylacetate=3/2) to give the title compound (0.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:24])[NH:20][C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:27]([F:30])([F:29])[F:28])[CH:4]=1.Cl.Cl[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:24])[N:20]([CH2:33][CH2:34][N:35]5[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)[C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:27]([F:30])([F:29])[F:28])[CH:4]=1
Reactant: ClCCN1CCCCC1
Reactant: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)NC4=O)ccc32)c(C(F)(F)F)c1
Agent: Cl
Product: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)N(CCN5CCCCC5)C4=O)ccc32)c(C(F)(F)F)c1

Procedure:
(5Z)-5-[(1-{[4-(Methyloxy)-2-(trifluoromethyl)phenyl]methyl}-1H-indazol-5-yl)methylidene]-3-(2-piperidin-1-ylethyl)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 8) and 1-(2-chloroethyl)piperidine hydrochloride following General Procedure H.