Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:21][CH2:22][CH2:23][CH2:24]O>C(Cl)Cl>[Br:21][CH2:22][CH2:23][CH2:24][O:19][C:18](=[O:20])[C@H:9]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: OCCCBr
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)OCCCBr
Temperature: 0 °C
Reaction time: 12 h
Yield: 79.6 %

Procedure:
N-Boc-Homophenylalanine (5.00 g, 17.9 mmol) and 3-bromo-1-propanol (1.60 mL, 17.7 mmol) were dissolved in CH2Cl2 (25 mL) and the mixture was cooled to 0° C. A solution of N,N-dicyclohexylcarbodiimide (4.80 g, 23.3 mmol) and N,N-dimethylaminopyridine (0.23 g, 1.90 mmol) in CH2Cl2 (25 mL) was slowly added and the reaction was slowly warmed to room temperature and stirred for 12 hours. The dicyclohexylurea was filtered off and the mother liquor was concentrated and purified by flash chromatography (Hexane/EtOAc 8:2) affording N-Boc-Homophenylalanine 3-bromopropyl ester as a clear oil (5.64 g, 79%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]2[C:10]=1[CH:9]=[N:8][NH:7][C:6]2=[S:11].[Na].[CH3:13]I>CO>[CH3:1][C:2]1[N:3]=[CH:4][N:5]2[C:10]=1[CH:9]=[N:8][N:7]=[C:6]2[S:11][CH3:13]
Reactant: Cc1ncn2c(=S)[nH]ncc12
Reactant: CI
Agent: [Na]
Solvent: CO
Product: CSc1nncc2c(C)ncn12
Reaction time: 0.5 h

Procedure:
A 1.66 gm. portion of 8-methyl-imidazo[1,5-d]-as-triazine-4(3H)-thione is added to a solution of 0.23 gm. of sodium in 10 ml. of methanol. A 0.75 ml. portion of methyl iodide is added, the mixture is allowed to stand for 30 minutes and then evaporated to dryness. The product is chromatographed on a silica gel column. The appropriate fractions are recrystallized from acetone giving the desired product, m.p. 128°-129° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:17]([O-])=O)[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:6]=2.[Cl-].[NH4+].C(O)C>[Fe].O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH2:17])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:6]=2
Reactant: O=[N+]([O-])c1cc(Br)cc2nn(C3CCCCO3)cc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cc(Br)cc2nn(C3CCCCO3)cc12
Temperature: 80 °C
Yield: 72.5 %

Procedure:
6-Bromo-4-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (6 g, 18.40 mmol), iron filings (3.29 g, 58.9 mmol) and ammonium chloride (0.492 g, 9.20 mmol) were weighed to a 250 ml flask and ethanol (60 ml) then water (18 ml) was added. The reaction was heated to 80° C. for 2.5 hr. The reaction mixture was cooled. 100 ml ethyl acetate and 50 ml water was added. There was no visible separation of layers so the reaction was evaporated to remove the ethyl acetate and ethanol. 250 ml ethyl acetate was then added and the organic layer was washed with a further 50 ml water, before passing through a hydrophobic frit. The organic layer was evaporated to dryness and purified by column chromatography on silica (120 g silica column, ISCO companion technology) eluting with a gradient of 1-2% methanol in DCM over 25 minutes. Fractions containing desired material were combined and evaporated to dryness to afford the title compound (3.95 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][C:13](C3C4C(=CC=C(C(F)(F)F)C=4)NN=3)=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[F:29][C:30]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:31]=1[C:32](Cl)=[O:33].[Sn](Cl)(Cl)(Cl)Cl>C1C=CC=CC=1.O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][C:13]([C:32](=[O:33])[C:31]3[C:30]([F:29])=[CH:38][CH:37]=[CH:36][C:35]=3[F:39])=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1cccc(F)c1)c1ccc(-c2n[nH]c3ccc(C(F)(F)F)cc23)[nH]1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: O=C(Nc1cccc(F)c1)c1ccc(C(=O)c2c(F)cccc2F)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.2 %

Procedure:
To a mixture of 1H-pyrrole-2-carboxylic acid (3-fluoro-phenyl)-amide (1 g, 4.9 mmol) (Example 55) and 2,6-difluro-benzoyl chloride 1.5 g, 8.8 mmol) (Aldrich, Milwaukee, Wis.) in benzene (10 mL) at room temperature was added a solution of tin (IV) chloride (1 mL, 2.26 g, 8.6 mmol). After stirring at room temperature for overnight, the reaction was diluted with water and ethyl acetate. The organic layer was washed with 2N NaOH, dried and purified on a silica gel column to give 205 mg of 5-(2,6-difluro-benzoyl)-1H-pyrrole-2-carboxylic acid (3-fluoro-phenyl)-amide as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[C:10]1[CH2:9][CH2:8][CH:7]([N:25]([CH3:27])[CH3:26])[CH2:6][C:5]2=1.C([Li])(C)(C)C.CN(OC)[C:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[OH-].[Na+]>O1CCCC1>[C:35]([C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([Si:15]([CH:19]([CH3:20])[CH3:21])([CH:16]([CH3:18])[CH3:17])[CH:22]([CH3:24])[CH3:23])[C:10]1[CH2:9][CH2:8][CH:7]([N:25]([CH3:26])[CH3:27])[CH2:6][C:5]2=1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1c2c(c3cc(Br)ccc31)CC(N(C)C)CC2
Reactant: CON(C)C(=O)c1ccccc1
Agent: [Li]C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1c2c(c3cc(C(=O)c4ccccc4)ccc31)CC(N(C)C)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
To a solution of 0.50 gm (1.11 mMol) 6-bromo-3-(dimethyl)amino-9-triisopropylsilyl-1,2,3,4-tetrahydro-9H-carbazole in 50 mL tetrahydrofuran at −78° C. were added 1.96 mL (3.33 mMol) t-butyllithium (1.7 M in pentane) and the resulting dark solution was allowed to stir for 30 minutes. To this mixture were then added 0.20 gm (1.22 mMol) N-methyl-N-methoxybenzamide and the reaction mixture was allowed to warm to room temperature over 1 hour. The reaction mixture was then treated with 0.1 N sodium hydroxide and then extracted well with chloroform. The organic phases were combined, dried over potassium carbonate and concentrated under reduced pressure to give 0.48 gm (91%) of the desired compound as a red-orange oil.
Reaction SMILES: [C:1]1([C@@H:7]([OH:25])[C@@H:8]([N:10](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)=O.[H][H]>CO.[Pd]>[CH3:9][C@@H:8]([NH2:10])[C@@H:7]([OH:25])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@@H]([C@H](O)c1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: C[C@@H](N)[C@@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To remove the benzyl group, 3.9 mmol of (1R,2S)-1-phenyl-2-(N,N-dibenzylamino)-1-propanol are dissolved in 5 ml of methanol. This solution is added to a mixture of 40 ml of methanol, 10.6 g of formic acid and 50 mg of palladium black. The air is displaced from the reaction vessel using hydrogen. After hydrogenation for 1 hour, the palladium catalyst is filtered off, and the solution is concentrated in vacuo. The residue is taken up in 10 ml of methanol and stirred with 1 g of silica gel and 5 drops of concentrated hydrochloric acid at room temperature for 1 hour. The residue obtained after removal of the silica gel by filtration and concentration of the filtrate is purified by chromatography. 243 mg (=60% of theory) of analytically pure norephedrine are obtained.
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1([S:9][CH2:10][CH2:11][CH3:12])[CH2:8][CH2:7]1)(=[O:5])[CH3:4].[Cl:13][C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[CH:16]=O.C(O)C>O.ClCCl>[CH2:10]([S:9][C:6]1([C:3]([CH:4]=[CH:16][C:15]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:14]=2[Cl:13])=[O:5])[CH2:8][CH2:7]1)[CH2:11][CH3:12]
Reactant: CCCSC1(C(C)=O)CC1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CCCSC1(C(=O)C=Cc2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 97.6 %

Procedure:
5 pellets of solid sodium hydroxide are added at room temperature to a mixture of 41.7 g (0.26 mol) of 1-acetyl-1-propylmercapto-cyclopropane, 46 g (0.26 mol) of 2,4-dichlorobenzaldehyde, 130 ml of ethanol and 30 ml of dichloromethane. The mixture is stirred for 14 hours at room temperature. 50 ml of water are added, and the oil phase is separated off and taken up in dichloromethane. The organic phase is washed with water, dried over sodium sulphate and concentrated by removing the solvent under reduced pressure. In this manner, 80 g (97% of theory) of 2,4-dichlorophenylethenyl 1-propylmercaptocyclopropyl ketone (cis/trans isomers) are obtained in the form of an oily product.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[Cl-].[Mg+2].[Cl-].S(Cl)(Cl)=O.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28](O)=[O:29])=[CH:22][C:21]=1[O:31][CH3:32]>O.CN(C)C=O>[CH3:32][O:31][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][C:20]=1[O:19][CH3:18])[CH:26]=[CH:27][C:28]([NH:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([OH:10])=[O:9])=[O:29]
Reactant: Nc1ccccc1C(=O)O
Reactant: COc1ccc(/C=C/C(=O)O)cc1OC
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: O
Product: COc1ccc(C=CC(=O)Nc2ccccc2C(=O)O)cc1OC
Temperature: 25 °C
Yield: 75.8 %

Procedure:
Into 15 ml of dimethylformamide were dissolved with heating 2.06 g (0.015 mol) of anthranilic acid and 2.7 g of magnesium chloride (anhydrous), and the resulting solution was cooled to room temperature. To 10 ml of dimethylformamide were added in order 0.78 ml of thionyl chloride and 2.08 g (0.01 mol) of 3',4'-dimethoxycinnamic acid, during which the reaction system was stirred and cooled with ice and water. After being stirred for additional 15 minutes, the resulting mixture was added dropwise to the above solution, with stirring at room temperature. After the completion of the dropping. the reaction mixture was stirred for additional 1.5 hours, and then treated in the same manner as in Example 2. There was obtained 2.48 g (yield: 75.8%) of N-(3',4'-dimethoxycinnamoyl)-anthranilic acid. Melting point: 209°-211° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH:22]=O)[CH:18]=[CH:17]2.C([O:26][C:27](=O)[C:28](=[O:33])[CH2:29][C:30](=[O:32])[CH3:31])C>C(O)C>[C:30]([C:29]1[CH:22]([C:19]2[CH:18]=[CH:17][C:16]3[C:21](=[C:12]([OH:11])[CH:13]=[CH:14][CH:15]=3)[N:20]=2)[N:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)[C:27](=[O:26])[C:28]=1[OH:33])(=[O:32])[CH3:31]
Reactant: O=Cc1ccc2cccc(O)c2n1
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: Nc1ccc2[nH]cnc2c1
Solvent: CCO
Product: CC(=O)C1=C(O)C(=O)N(c2ccc3[nH]cnc3c2)C1c1ccc2cccc(O)c2n1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
1H-Benzoimidazol-5-ylamine (1 mmol) and 8-Hydroxy-quinoline-2-carbaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 2,4-Dioxo-pentanoic acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(O[C@@H]1[O:43][C@H:42]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[C@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:27]1[O:28][C:29](=[O:31])[CH3:30])(=O)C.[CH2:49](N(CC)CC)C>C(Cl)Cl>[C:29]([O:28][C@@H:27]1[C@@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@@H:42]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[O:43][C@H:1]1[O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:49])=[CH:5][CH:4]=1)(=[O:31])[CH3:30]
Reactant: COc1ccc(O)cc1
Reactant: CCN(CC)CC
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(O[C@@H]2O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Reaction time: 4 h
Yield: 92 %

Procedure:
p-methoxyphenol (20.5 mmol, 2.5 g) and trimethylsilyl trifluoromethanesulfonate (0.25 mL) were added to a solution of β-D-galactose pentaacetate (5.0 g, 12.8 mmol) in anhydrous CH2Cl2 at 0° C. under nitrogen. After 4 hours at 0° C., the reaction mixture was neutralized by addition of triethylamine (1 mL) and concentrated under reduced pressure. Purification by chromatography on silica gel (ethyl acetate-petroleum ether, v/v 1:3→1.5:1) afforded 6 as an amorphous white solid in 92% yield (5.35 g). Litt22 [αD]=+9.6° (c 0.54, CHCl3); [αD]23=+3° (c 1, CHCl3); 1H NMR (500 MHz, CDCl3): δ2.01, 2.06, 2.08 and 2.19 (4 s, 3H each, 4 OAc), 3.78 (s, 3H, OMe), 4.01 (m, 1H, H-5), 4.16 (dd, 1H, J5,6b 6.5 Hz, J6a,6b 11.3 Hz, H-6b), 4.23 (dd, 1H, J5,6a 6.9 Hz, H-6a), 4.92 (d, 1H, J1,2 8.0 Hz, H-1), 5.09 (dd, 1H, J2,3 10.4 Hz, J3,4 3.3 Hz, H-3), 5.5.44-5.48 (m, 2H, H-2 and H-4), 6.80 and 6.96 (2 d, 2H each, Ph).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:36][C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[N:12]([C:14]2[CH:15]=[C:16]([N:20]3[S:24](=[O:26])(=[O:25])[N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:22](=[O:35])[CH2:21]3)[CH:17]=[CH:18][CH:19]=2)[CH:13]=1.[Cl:52][C:53]1[N:54]=[N:55][C:56](Cl)=[CH:57][CH:58]=1>>[Cl:52][C:53]1[N:54]=[N:55][C:56]([C:40]2[CH:41]=[CH:42][C:37]([CH2:36][C:11]3[N:12]([C:14]4[CH:15]=[C:16]([N:20]5[S:24](=[O:25])(=[O:26])[N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:33])[CH3:34])[C:22](=[O:35])[CH2:21]5)[CH:17]=[CH:18][CH:19]=4)[CH:13]=[C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[N:10]=3)=[CH:38][CH:39]=2)=[CH:57][CH:58]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC1(C)OB(c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3cccc(N4CC(=O)N(COCC[Si](C)(C)C)S4(=O)=O)c3)cc2)OC1(C)C
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Cl)nn4)cc3)c2)S1(=O)=O

Procedure:
5-(3-{4-(2,4-Dichloro-phenyl)-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-imidazol-1-yl}-phenyl)-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (385 mg, 0.5 mmol) was treated as described in general procedure G using 3,6-dichloropyridazine (149 mg, 1 mmol) to give 5-{3-[2-[4-(6-chloro-pyridazin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one.
Reaction SMILES: [CH3:1][CH:2]([S:5][C:6]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10]C=1C#N)[CH2:3][CH3:4].[OH-:18].[Na+].[CH2:20]([OH:22])[CH3:21].Cl>O>[CH3:1][CH:2]([S:5][C:6]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:21]=1[C:20]([OH:18])=[O:22])[CH2:3][CH3:4]
Reactant: CCC(C)Sc1cc(C(F)(F)F)ccc1C#N
Reactant: [OH-]
Reactant: CCO
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCC(C)Sc1cc(C(F)(F)F)ccc1C(=O)O

Procedure:
2-(1-Methylpropylsulphenyl)-4-trifluoromethylbenzonitrile (8.6 g), 10M sodium hydroxide (120 ml) and ethanol were combined and heated at reflux for 24 hours. The cooled mixture was poured into water and acidified to pH 1 with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate. The organic phase was washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness yielding 2-(1-methylpropylsulphenyl)-4-trifluoromethylbenzoic acid (8.1 g) as a white solid, mp. 99.8°-101° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=[C:11]2[C:31]2[CH:32]=[N:33][C:34]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:35][C:36]=2[O:37][CH2:38][CH3:39])=[O:9])[CH2:4][CH2:3]1.[C:44](Cl)(Cl)=[O:45].[NH:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1>>[C:40]([C:34]1[N:33]=[CH:32][C:31]([C:11]2[N:10]([C:8]([N:5]3[CH2:4][CH2:3][CH:2]([NH:1][C:44]([N:48]4[CH2:52][CH2:51][CH2:50][CH2:49]4)=[O:45])[CH2:7][CH2:6]3)=[O:9])[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=2)=[C:36]([O:37][CH2:38][CH3:39])[CH:35]=1)([CH3:42])([CH3:41])[CH3:43]
Reactant: C1CCNC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N)CC1
Reactant: O=C(Cl)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(NC(=O)N2CCCC2)CC1

Procedure:
(4-Amino-piperidin-1-yl)-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-methanone (example 204) was reacted with phosgene (Fluka) and pyrrolidine (Aldrich) to give the title product. LC-MS (ES+) 719 [(M+H)+].
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl.CN(C=O)C>[Cl:21][C:7]([C:6]1[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:5]=1[O:4][C:1](=[O:3])[CH3:2])=[O:8]
Reactant: CC(=O)Oc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc(C(F)(F)F)ccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-acetoxy-4-trifluoromethyl-benzoic acid (180 mg, 0.73 mmol) in CH2Cl2 (6 mL) were added oxalyl chloride (0.08 mL, 0.91 mmol) and DMF (1 drop). The reaction mixture was stirred at room temperature for 1 hour. CH2Cl2 and excess oxalyl chloride were removed in vacuo. Acetic acid 2-chlorocarbonyl-5-trifluoromethylphenyl ester was obtained as a colorless oil (190 mg) and used in the following step without further purification. To a stirred solution of [1-Methyl-6-(5-methylaminopyridin-2-yloxy)-1H-indol-2-yl]{4-[4-(2,2,2-tri-fluoroethoxy)benzyl]piperazin-1-yl}methanone (340 mg, 0.6 mmol) in AcOEt (4 mL) were added triethylamine (0.13 mL, 0.91 mmol) and acetic acid 2-chlorocarbonyl-5-trifluoromethyl-phenyl ester (190 mg, 0.73 mmol) in AcOEt (3 mL) under ice cooling. The reaction mixture was stirred for 10 minutes at 0° C. Water was added to the reaction mixture, and the aqueous layer was extracted with AcOEt. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=50:1) to afford 0.46 g of the title compound as a white powder.
Reaction SMILES: [Cl:1][S:2](Cl)(=[O:4])=[O:3].C[OH:7].[CH2:8]([O:10][CH2:11]C)[CH3:9]>>[CH3:11][O:10][C:8](=[O:7])[CH2:9][S:2]([Cl:1])(=[O:4])=[O:3]
Reactant: CCOCC
Reactant: O=S(=O)(Cl)Cl
Reactant: CO
Product: COC(=O)CS(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To chlorosulfonyl chloride (3.34 g, 17.9 mmol) in diethyl ether (30 mL) is added at 0° C. methanol (800 μL, 19.7 mmol). The resulting mixture is stirred at 0° C. during 1 h and the solvent is evaporated to give the title compound.
Reaction SMILES: C1O[C:16]23[O:17][CH2:18][O:19][C:15]2=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)=[C:4]([NH2:21])[CH:3]3O1.[CH:22]([OH:24])=[O:23].[CH:25]([NH2:27])=O>>[CH2:18]1[O:17][C:16]2[CH:3]=[C:4]3[C:5]([C:6]([C:8]4[CH:9]=[CH:10][C:11]5[O:23][CH2:22][O:24][C:12]=5[CH:13]=4)=[N:27][CH:25]=[N:21]3)=[CH:14][C:15]=2[O:19]1
Reactant: NC1=C(C(=O)c2ccccc2)C=C2OCOC23OCOC13
Reactant: O=CO
Reactant: NC=O
Product: c1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2n1)OCO3
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3,4-(methylenedioxy)-2-amino-4,5-(methylenedioxy)benzophenone (100 mg, 0.32 mmol) in formamide (1.0 mL) was added formic acid (0.5 mL). The resulting mixture was refluxed under argon for 45 min, cooled to rt, poured into ice water (10 mL), and stirred for 30 min. The resulting precipitate was collected by filtration and the solid was dissolved in ethyl acetate. The solution was washed with water and brine, dried over anhydrous MgSO4 and the solvent was removed in vacuo. The crude product was purified by chromatography on silica gel. Elution with hexane:acetone (70:30) gave the title compound (52 mg); mp 180-185° C. 1H NMR (DMSO-d6) 9.05 (s, 1H), 7.40 (s, 1H), 7.33 (s, 1H), 7.28 (s, 1H), 7.23 (d, J=7.98, 1H), 7.10 (d, J=7.98, 1H), 6.25 (s, 2H), 6.10 (s, 2H). Anal. calcd. for C16H10N2O4: C, 65.31; H, 3.43; N, 9.52. Found: C, 65.07; H, 3.59; N, 9.30.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@H:12]([OH:14])[CH2:11][N:10]2[C:15]([C:17]2([CH3:20])[CH2:19][CH2:18]2)=[O:16])=[O:8])[CH2:5][CH2:4]1)#[N:2].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.Cl>CN(C)C1C=CN=CC=1.ClCCl.O>[C:1]([C:3]1([NH:6][C:7]([C@H:9]2[N:10]([C:15]([C:17]3([CH3:20])[CH2:19][CH2:18]3)=[O:16])[CH2:11][C@@H:12]([O:14][S:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:29])=[O:28])[CH2:13]2)=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: CC1(C(=O)N2C[C@@H](O)C[C@H]2C(=O)NC2(C#N)CC2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC1(C(=O)N2C[C@@H](OS(=O)(=O)c3ccccc3)C[C@H]2C(=O)NC2(C#N)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.5 %

Procedure:
(2S,4S)-4-Hydroxy-1-(1-methyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (62.0 g, 224 mmol) and 4-(dimethylamino)pyridine (98%, 1.5 g, 12.0 mmol) were dissolved in dichloromethane (370 mL), benzenesulfonyl chloride (31.1 mL, 242 mmol), followed by triethylamine (49.8 mL, 358 mmol) were added at room temperature and the mixture was stirred for 16 h. After that, it was diluted with water (140 mL) and acidified by addition of hydrochloric acid (25% m/m, 21.4 mL). The phases were separated and the organic layer was washed with water (160 mL). The combined aqueous phases were extracted with dichloromethane (160 mL), the combined organic extracts were concentrated in vacuo to a volume of 430 mL. The solvent was exchanged via continuous distillation in vacuo (internal temperature 40° C., 670-170 mbar) to ethanol (670 mL added), the overall volume was kept constant (430 mL). The resulting solution was allowed to cool to room temperature and seed crystals (ca. 10 mg) were added to initiate crystallization. After crystallization had started, the suspension was stirred for 30 min at room temperature, heptane (430 mL) was added within 50 min and it was stirred for 12 h. The suspension was then filtered, the precipitate was washed with heptane/ethanol 2:1 (v/v, 321 mL) and heptane (107 mL) and dried in vacuo at 40° C. to yield the title compound as a white crystalline solid (80.0 g, 85%). MS (ESI & APCI): m/z=418.1 [M+H]+. 1H NMR (CDCl3, 600 MHz): δ 0.59-0.64 (m, 1H), 0.65-0.69 (m, 1H), 0.80-0.90 (m, 1H), 0.99-1.05 (m, 1H), 1.12-1.21 (m, 2H), 1.30 (s, 3H), 1.47-1.53 (m, 2H), 2.15 (ddd, J=5.8 Hz, 9.2 Hz, 14.6 Hz, 1H), 2.70 (br d, J=14.0 Hz, 1H), 3.83 (dd, J=3.8 Hz, 12.3 Hz, 1H), 4.08 (dd, J=5.3 Hz, 12.4 Hz, 1H), 4.55 (br s, 1H), 5.04-5.08 (m, 1H), 7.49 (br s, 1H), 7.61 (t, J=7.8 Hz, 2H), 7.70 (t, J=7.5 Hz, 1H), 7.96 (d, J=7.6 Hz, 2H).
Reaction SMILES: [BH4-].[Na+].[N:3]1[N:4]([CH2:12][CH2:13][C:14]#[C:15][C:16]2[N:21]=[C:20]([C:22](=[O:24])[CH3:23])[CH:19]=[CH:18][CH:17]=2)[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12>CO>[N:3]1[N:4]([CH2:12][CH2:13][C:14]#[C:15][C:16]2[N:21]=[C:20]([CH:22]([OH:24])[CH3:23])[CH:19]=[CH:18][CH:17]=2)[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12
Reactant: CC(=O)c1cccc(C#CCCn2nc3ccccc3n2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cccc(C#CCCn2nc3ccccc3n2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
NaBH4 (99 mg, 1.6 mmol) was added to a solution of 1-[6-(4-benzotriazol-2-yl-but-1-ynyl)-pyridin-2-yl-]-ethanone (380 mg, 1.31 mmol) in MeOH (5 mL) at 0° C. The reaction mixture was stirred at room temperature for 30 min., quenched by the addition of water at 0° C. and extracted twice with DCM. The organic phase was washed with water, dried over Na2SO4, filtered and evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 202 mg (0.69 mmol, 53%) of 1-[6-(4-benzotriazol-2-yl-but-1-ynyl)-pyridin-2-yl]-ethanol as a colorless oil.