Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(CCC1C=CC([C:12]2[C:13]([CH3:43])([CH3:42])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)=CC=1)(O)=O.B([C:47]1[CH:48]=[C:49](/[CH:53]=[CH:54]/[C:55]([OH:57])=[O:56])[CH:50]=[CH:51][CH:52]=1)(O)O.B(O)O>>[C:55]([CH2:54][CH2:53][C:49]1[CH:48]=[C:47]([C:12]2[C:13]([CH3:43])([CH3:42])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:52]=[CH:51][CH:50]=1)([OH:57])=[O:56]
Reactant: O=C(O)/C=C/c1cccc(B(O)O)c1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(CCC(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: OBO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6cccc(CCC(=O)O)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for compound (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(2-carboxyethyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (example 4a) using (E)-3-(3-boronophenyl)acrylic acid as the reactant boronic acid. The product was isolated as a white solid (34.4 mg, 80%). LCMS: m/e 585.63 (M−H)−, 6.47 min (method 3). 1H NMR (400 MHz, <DMSOmix>) δ ppm 0.89 (d, 6H), 0.97 (s, 6H), 1.00 (s, 3H), 1.01-1.66 (m, 17H), 1.68 (s, 3H), 1.80-1.94 (m, 2H), 2.02-2.12 (m, 1H), 2.13-2.22 (m, 1H), 2.26-2.39 (m, 1H), 2.55-2.60 (m, 2H), 2.83 (t, J=7.62 Hz, 2H), 2.94-3.07 (m, 1H), 4.58 (br. s., 1H), 4.71 (s, 1H), 5.20 (d, J=4.10 Hz, 1H), 6.88-6.98 (m, 2H), 7.08 (d, J=6.44 Hz, 1H), 7.13-7.22 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1[C:19]([CH3:20])=[CH:18][C:17]([O:21][CH2:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:16]1.ClC1C=CC=C(C(OO)=[O:36])C=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9]([CH2:10][C:11]([F:14])([F:12])[F:13])=[O:36])=[CH:4][C:3]=1[N:15]1[C:19]([CH3:20])=[CH:18][C:17]([O:21][CH2:22][CH2:23][C:24]([F:25])([F:26])[F:27])=[N:16]1
Reactant: Cc1cc(F)c(-n2nc(OCCC(F)(F)F)cc2C)cc1SCC(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(F)c(-n2nc(OCCC(F)(F)F)cc2C)cc1S(=O)CC(F)(F)F
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
0.29 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-methyl-3-(3,3,3-trifluoropropoxy)pyrazole was dissolved in 10 mL of chloroform, and 0.17 g of m-chloroperbenzoic acid (purity: 75%) was slowly added under cooling with ice. After stirring for 30 minutes under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate:hexane=1:2) to obtain 0.30 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-5-methyl-3-(3,3,3-trifluoropropoxy)pyrazole.
Reaction SMILES: [I-].[K+].[I:3]([C:5]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])=O.C(O)(=O)C>O>[I:3][C:5]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=Ic1cc([N+](=O)[O-])ccc1C(=O)O
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc([N+](=O)[O-])cc1I
Temperature: 23 °C
Reaction time: 1 h

Procedure:
Solid potassium iodide (55 g, 0.33 mol) was added in one portion to a suspension of 2-iodosyl-4-nitro-benzoic acid I-1a (54.9 g, 0.18 mol) in water (250 ml) and glacial acetic acid (50 ml). Over the next 5-10 minutes, the solids gradually went into solution and the solution turned from off-white to red. After stirring for one hour at 23° C., gaseous sulfur dioxide was bubbled through the reaction mixture until the red color dissipated and a pale green suspension had formed. The solids were collected by filtration, co-evaporated from toluene (3×250 ml), and dried in vacuo to affort 2-iodo-4-nitrobenzoic acid I-1b (33 g, 64%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[C:5]([N+:14]([O-])=O)=[CH:4][N:3]=1.Cl>C(O)C.[Fe]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH:11]([CH3:12])[CH3:13])[C:5]([NH2:14])=[CH:4][N:3]=1
Reactant: CC(C)CCNc1nc(Cl)ncc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CC(C)CCNc1nc(Cl)ncc1N
Temperature: 25 °C
Yield: 71.2 %

Procedure:
To a stirred solution of 2-chloro-N-(3-methylbutyl)-5-nitropyrimidin-4-amine (800 mg, 3.27 mmol) in ethanol (40 ml) was added iron powder (1.8 g). The resulting mixture was heated to reflux before 2 N aqueous hydrochloric acid (4 mL) was added in small portion over 10 min. The reaction was then refluxed for 2 h. The reaction mixture was cooled to rt, filtered to remove inorganic material. The solution was then concentrated under reduced pressure to afforded the desired compound (500 mg), which was used for next step without any further purifications. 1H NMR (CDCl3, 300 MHz) δ 0.92 (d, J=6.8 Hz, 6H), 1.42-1.80 (m, 3H), 3.42-3.60 (m, 2H), 5.01-5.15 (br s 1H), 7.60 (s, 1H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].CCOCC.C([O:12][C:13]([C@H:15]1[CH2:19][CH2:18][C@@H:17]([C:20]2[CH:25]=[C:24]([F:26])[C:23]([F:27])=[C:22]([F:28])[CH:21]=2)[N:16]1[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=O)C.Cl>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].C(OCC)(=O)C>[CH2:29]([N:16]1[C@H:17]([C:20]2[CH:25]=[C:24]([F:26])[C:23]([F:27])=[C:22]([F:28])[CH:21]=2)[CH2:18][CH2:19][C@@H:15]1[C:13]1([OH:12])[CH2:2][CH2:1]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)[C@H]1CC[C@@H](c2cc(F)c(F)c(F)c2)N1Cc1ccccc1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: OC1([C@H]2CC[C@@H](c3cc(F)c(F)c(F)c3)N2Cc2ccccc2)CC1
Reaction time: 15 h

Procedure:
Under a nitrogen atmosphere and at room temperature, ethyl magnesium bromide (8.49 mL, tetrahydrofuran 1M solution) was added dropwise over 1 hour into an ether (10 mL) solution of (2R,5S)-1-benzyl-5-(3,4,5-trifluorophenyl)pyrrolidine-2-carboxylic acid ethyl ester (1.03 g) and titanium tetraisopropoxide (209 μL). The resultant was stirred at the same temperature for 15 hours. The reaction solution was ice-cold, and 1 N hydrochloric acid was added, stirring was continued for 30 minutes at the same temperature. Ethyl acetate was added, and the organic layer was partitioned, and after washing the organic layer with brine, the resultant was dried with magnesium sulfate. The solvent was removed under a vacuum, and the residue was purified by silica gel column chromatography, and the title compound (602 mg) was obtained. The physical property values are as follows.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([CH2:13]O)[N:10]=[C:9]1[CH2:15][CH2:16][CH2:17][CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:39]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([CH2:13][Br:39])[N:10]=[C:9]1[CH2:15][CH2:16][CH2:17][CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCc1nc(CO)cn1C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCc1nc(CBr)cn1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
To a solution of 1-tert-butoxycarbonyl-2-n-butyl-4-(hydroxymethyl)imidazole (4.43 g) in dichloromethane (80 ml) was added triphenylphosphine (5.48 g) followed by carbon tetrabromide (6.93 g) at ambient temperature and the mixture was stirred for 30 minutes. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=4:1) to give 1-tert-butoxycarbonyl-2-n-butyl-4-(bromomethyl)imidazole (5.09 g) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:29]([OH:31])=O)=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:32]([O:39][CH2:40][CH2:41][NH:42][CH3:43])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].[Si](OCCN(C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2C=CC=CC=2C2C=CC=CC=2)N=1)=O)(C(C)(C)C)(C)C>>[Si:32]([O:39][CH2:40][CH2:41][N:42]([CH3:43])[C:29]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]=1)=[O:31])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:33])[CH3:34]
Reactant: O=C(O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CNCCO[Si](C)(C)C(C)(C)C
Agent: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Product: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Yield: 47.9 %

Procedure:
5-Benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]methyl-amide (29-02) (2 g, 47.85%) was synthesized from 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (28-02) (3 g, 6.84 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amine (8-a) as a gummy solid (1.4 g, 7.53 mmol) following the procedure as described for 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (9-01).
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:6]=[C:7]([C@@H:15]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]>CO.N1C(C)=CC=CC=1C>[Cl:4][C:5]1[CH:6]=[C:7]([C@@H:15]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=[N:2][OH:3])[CH2:29][CH2:28]2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: NO
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)Nc2ccc(Cl)cn2)cc1Cl
Agent: Cl
Solvent: CO
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=NO)CC2)C(=O)Nc2ccc(Cl)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
A solution of hydroxylamine hydrochloride (26.0 mg, 0.36 mmol) in methanol (0.7 mL) and 2,6-lutidine (0.7 mL) was treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-chloro-pyridin-2-yl)-3-(4-oxo-cyclohexyl)-propionamide (prepared as in Example 63, 114 mg, 0.24 mmol). The reaction mixture was stirred at 25° C. for 30 min and was then concentrated in vacuo to remove methanol. The resulting residue was suspended in ethyl acetate (10 mL), washed with water 1×5 mL), dried over magnesium sulfate, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 65/35 hexanes/ethyl acetate to 2/8 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-chloro-pyridin-2-yl)-3-(4-hydroxyimino-cyclohexyl)-propionamide (105 mg, 90%) was a white powder: [α]23589=−23.03° (c=0.33 chloroform); EI-HRMS m/e calcd for C21H23Cl2N3O4S (M+H)+ 484.0859. found 484.0862.
Reaction SMILES: ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[F:13][C:14]([F:22])([F:21])[CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17].CCN(C(C)C)C(C)C.ClC([O-])=O.C(OC([NH:43][C@@H:44]1[CH2:48][CH2:47][N:46]([C:49]2[CH:68]=[C:67]([Cl:69])[CH:66]=[CH:65][C:50]=2[CH2:51][N:52]2[CH2:57][CH2:56][N:55]([C:58](OC(C)(C)C)=[O:59])[CH2:54][CH2:53]2)[CH2:45]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:43][C@@H:44]1[CH2:48][CH2:47][N:46]([C:49]2[CH:68]=[C:67]([Cl:69])[CH:66]=[CH:65][C:50]=2[CH2:51][N:52]2[CH2:57][CH2:56][N:55]([C:58]([O:20][CH:15]([C:16]([F:19])([F:18])[F:17])[C:14]([F:22])([F:21])[F:13])=[O:59])[CH2:54][CH2:53]2)[CH2:45]1
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2cc(Cl)ccc2CN2CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: N[C@@H]1CCN(c2cc(Cl)ccc2CN2CCN(C(=O)OC(C(F)(F)F)C(F)(F)F)CC2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 28.4 %

Procedure:
A round bottom flask was charged with triphosgene (18 mg, 0.061 mmol), CH2Cl2 (1 mL), and 1,1,1,3,3,3-hexafluoropropan-2-ol (30 mg, 0.202 mmol). DIPEA (104 μL, 0.606 mmol) was added to this solution dropwise and the chloroformate was allowed to form at room temperature for 2 h. A separate flask was charged with (R)-tert-butyl 4-(2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-4-chlorobenzyl)piperazine-1-carboxylate (100 mg, 0.202 mmol) and CH2Cl2 (3 mL) and cooled to 0° C. Trifluoroacetic acid (1 mL) was added dropwise over 1 minute. The reaction was stirred at 0° C. for 15 min. The reaction was allowed to warm to room temperature. After 60 min, the reaction was concentrated under reduced pressure. Methanol was added and the solution was concentrated yielding crude diamine. The crude diamine was dissolved in CH2Cl2 (3 mL) and cooled to 4° C. DIPEA (150 μL, 0.876 mmol) was added followed by the chloroformate solution over 5 minutes. After stirring for 2 h at 0° C. the reaction was quenched by addition of sat Na2CO3 and extracted with CH2Cl2 (3×). The organics were dried (Na2SO4), filtered, and concentrated. The residue was chromatographed on a silica gel column (100% CH2Cl2 to 10% 2M NH3 in MeOH) and yielded (R)-1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(3-aminopyrrolidin-1-yl)-4-chlorobenzyl)piperazine-1-carboxylate (28 mg, 28%): 1H NMR 400 MHz (CDCl3) δ 7.29-7.22 (m, 1H), 6.92-6.76 (m, 2H), 5.82-5.66 (m, J=6.4 Hz, 1H), 3.54 (tddd, J=37.8, 22.2, 11.8, 6.2 Hz, 9H), 3.21 (ddd, J=15.3, 10.0, 5.8 Hz, 1H), 3.11-3.04 (m, 1H), 2.49-2.34 (m, 4H), 2.22 (ddd, J=19.5, 13.0, 6.6 Hz, 1H), 1.80 (dt, J=12.7, 6.4 Hz, 1H). LCMS (ESI, m/z): 489 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:17])[CH2:10][C:11]1[N:15]([CH3:16])[N:14]=[N:13][N:12]=1.[CH:18](O)=O>C(OCC)C>[CH3:1][N:2]1[C:3]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:9](=[O:17])[C:10]([C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)=[CH:18]1
Reactant: CNc1ccccc1C(=O)Cc1nnnn1C
Reactant: O=CO
Solvent: CCOCC
Product: Cn1nnnc1-c1cn(C)c2ccccc2c1=O
Temperature: 25 °C

Procedure:
A mixture of 1-(2-methylaminophenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanone (0.2 g) and formic acid (5 ml) was heated on a steam bath for 16 hours. The mixture was cooled to ambient temperature and diluted with diethyl ether (80 ml). The resulting precipitate was collected and crystallised from industrial methylated spirit to give the novel compound 1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone, m.p. 219°-221°, identical to the product of Example 1(a).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]([N:13]3[CH2:17][C@H:16]([NH:18][CH3:19])[C@@H:15]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)=[O:30]>>[CH3:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([O:31][C:29](=[O:30])[N:18]([C@@H:16]2[C@@H:15]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:14][N:13]([C:11]([CH:8]3[CH2:9][CH2:10][N:5]([CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[O:12])[CH2:17]2)[CH3:19])=[CH:33][CH:34]=1
Reactant: COc1ccc(OC(=O)Cl)cc1
Reactant: CN[C@H]1CN(C(=O)C2CCN(CC3CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Product: COc1ccc(OC(=O)N(C)[C@H]2CN(C(=O)C3CCN(CC4CC4)CC3)C[C@@H]2c2ccc(Cl)c(Cl)c2)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 2 (step b), the title compound rac-[(3R,4S)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-methoxy-phenyl ester was prepared from rac-(1-cyclopropylmethyl-piperidin-4-yl)-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-methanone instead of rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 4-methoxy-phenyl chloroformate instead of fluorophenyl chloroformate and was obtained as a colorless oil. MS m/e: 560.2 [M]+.
Reaction SMILES: [CH3:1][Li].[CH2:3]1[CH2:19][O:18][C:5]2([CH2:11][O:10][C:9]([CH3:17])([CH2:12][CH2:13][CH2:14][CH:15]=[O:16])[CH2:8][CH2:7][CH2:6]2)[O:4]1>CCOCC>[CH2:19]1[CH2:3][O:4][C:5]2([CH2:11][O:10][C:9]([CH2:12][CH2:13][CH2:14][CH:15]([OH:16])[CH3:1])([CH3:17])[CH2:8][CH2:7][CH2:6]2)[O:18]1
Reactant: [Li]C
Reactant: CC1(CCCC=O)CCCC2(CO1)OCCO2
Solvent: CCOCC
Product: CC(O)CCCC1(C)CCCC2(CO1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
Methyllithium (10 ml, 0.0184 mol, 1.84 M in hexane) is added dropwise to a solution of 6,6-ethylenedioxy-2-methyl-2-(4'-oxobutyl)-oxepane (3.3 g) in ether (150 ml) at 0° C. in a nitrogen atmosphere. The cooling bath is removed and the mixture is stirred for 0.5 hour at ambient temperature. The mixture is poured into cold satd. NaCl (300 ml). The ether layer is separated and the aqueous layer extracted with ether (3×50 ml). The ether phases are combined, dried (MgSO4) and the solvent is removed at reduced pressure. The crude product (3.6 g) is chromatographed on SilicAR CC-7 (70 g) in hexane. Elution with 15% ethyl acetate/hexane gives 6,6-ethylenedioxy-2-(4'-hydroxypentyl)-2-methyloxepane (15) as a clear colorless oil (3.3 g, 94%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][C:12]([C:14]3[C:19]([O:20][CH2:21][CH:22]=[CH2:23])=[CH:18][C:17]([CH3:24])=[CH:16][C:15]=3[O:25][C@@H:26]3[O:34][C@H:33]([CH2:35][OH:36])[C@@H:31]([OH:32])[C@H:29]([OH:30])[C@H:27]3[OH:28])=[O:13])[CH:8]=[CH:9][C:2]1=2.C(=O)=O.CC(C)=O.Cl[C:45]([O:47][CH3:48])=[O:46].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C(C)=CC(C)=CC=1C.ClCCl>[O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][C:12]([C:14]3[C:19]([O:20][CH2:21][CH:22]=[CH2:23])=[CH:18][C:17]([CH3:24])=[CH:16][C:15]=3[O:25][C@@H:26]3[O:34][C@H:33]([CH2:35][O:36][C:45]([O:47][CH3:48])=[O:46])[C@@H:31]([OH:32])[C@H:29]([OH:30])[C@H:27]3[OH:28])=[O:13])[CH:8]=[CH:9][C:2]1=2
Reactant: COC(=O)Cl
Reactant: C=CCOc1cc(C)cc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1C(=O)CCc1ccc2occc2c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C=O
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Solvent: CC(C)=O
Product: C=CCOc1cc(C)cc(O[C@@H]2O[C@H](COC(=O)OC)[C@@H](O)[C@H](O)[C@H]2O)c1C(=O)CCc1ccc2occc2c1
Yield: 87.2 %

Procedure:
3-(5-Benzo[b]furanyl)-2'-(β-D-glucopyranosyloxy)-6'-allyloxy-4'-methylpropiophenone (500 mg) is dissolved in 2,4,6-collidine (5 ml), and the mixture is cooled to 40° C. with dry ice-acetone, and thereto is added dropwise a solution of methyl chloroformate (114 mg) in dichloromethane (0.5 ml) with stirring. The mixture is stirred at 40° C. for one hour, and stirred at room temperature for 1.5 hour. The reaction mixture is poured into cold 10% aqueous citric acid solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with water, dried, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give 3-(5-benzo[b]furanyl)-2'-(6-O-methoxycarbonyl-β-D-glucopyranosyloxy)-6'-allyloxy-4'-methylpropiophenone (487 mg).
Reaction SMILES: [C:1]([C:3]1[C:4]2[N:41](COCC[Si](C)(C)C)[CH:40]=[N:39][C:5]=2[C:6]([CH2:30][C:31]2[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:38])=[N:7][C:8]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)=[C:12]([CH3:29])[CH:11]=1)#[N:2].C(=O)(O)[O-:51].[Na+]>S(=O)(=O)(O)O.O>[Cl:37][C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:38])[C:31]=1[CH2:30][C:6]1[C:5]2[N:39]=[CH:40][NH:41][C:4]=2[C:3]([C:1]([NH2:2])=[O:51])=[C:8]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)=[C:12]([CH3:29])[CH:11]=2)[N:7]=1
Reactant: Cc1cc(Nc2nc(Cc3c(Cl)cccc3Cl)c3ncn(COCC[Si](C)(C)C)c3c2C#N)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(Nc2nc(Cc3c(Cl)cccc3Cl)c3nc[nH]c3c2C(N)=O)ccc1N1CCNCC1
Temperature: 95 °C

Procedure:
To a solution of the product of Example 29A (120 mg, 0.17 mmol) in concentrated sulfuric acid (5 mL) was added water (1 mL) at 0° C. and the mixture was heated at 95° C. for 20 minutes. After cooling to ambient temperature, the mixture was diluted with water (3 mL), and the pH was adjusted to pH 8-9 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (3×20 mL). The combined organic phase was concentrated and the residue was purified via preparative HPLC using a gradient of 10/90 to 80/20 acetonitrile/water (containing 0.1% trifluoroacetic acid) to give the title compound. 1H NMR (DMSO-d6, 3 00 MHz): δ 13.55 (br, 1H), 11.66 (s, 1 H), 9.58 (s, 1 H), 8.67 (s, 1 H), 8.57 (s, 1 H), 7.81 (s, 1 H), 7.57-7.54 (m, 1 H), 7.41-7.36 (m, 1 H), 7.11 (dd, J=8.4, 2.1 Hz, 1 H), 7.05 (d, J=2.1 Hz, 1 H), 6.62 (d, J=8.4 Hz, 1 H), 4.69 (s, 2H), 3.23-3.22 (m, 4 H), 2.94-2.92 (m, 4 H), 2.14 (s, 3 H). MS: 510 (M+H+).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].Br[C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]([NH:26][C:27](=[O:29])[CH3:28])[CH3:25])=[CH:20][CH:19]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>O1CCOCC1>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:12][CH2:13][N:14]([C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]([NH:26][C:27](=[O:29])[CH3:28])[CH3:25])=[CH:20][CH:19]=3)[CH2:15][CH2:16]2)=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(C2CCNCC2)cc1
Reactant: CC(=O)N[C@@H](C)c1ccc(Br)cc1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1COCCO1
Product: CCCOc1ccc(C2CCN(c3ccc([C@H](C)NC(C)=O)cc3)CC2)cc1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
80 mg (0.37 mmol) 4-(4-Propoxy-phenyl)-piperidine (II.3) are added to a mixture of 88 mg (0.37 mmol) (S)—N-[1-(4-bromo-phenyl)-ethyl]-acetamide (III.1), 145 mg (97%, 1.46 mmol) sodium tert-butyrat, 44 mg (0.15 mmol) 2-(di-tert-butylphosphino)biphenyl and 33 mg (0.036 mmol) tris-(dibenzylidenaceton)-dipalladium(0) in 2.0 mL 1,4-dioxane. The mixture is stirred for 12 h at 70° C. After that time, the mixture is filtered over celite, the solvent is removed in vacuo and the residue is purified by HPLC (column: Waters XBridge 5 μM; eluent A: water+0.3% NH4OH, eluent B: MeOH) to yield the desired product.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)=[O:21])[CH2:3][CH2:2]1.[NH:29]1[CH2:33][CH2:32][CH2:31][C@@H:30]1[CH2:34][OH:35]>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:27][CH2:26][CH:25]([N:29]3[CH2:33][CH2:32][CH2:31][C@@H:30]3[CH2:34][OH:35])[CH2:24][CH2:23]2)=[O:21])[CH2:3][CH2:2]1
Reactant: OC[C@H]1CCCN1
Reactant: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(=O)CC1
Product: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(N2CCC[C@@H]2CO)CC1

Procedure:
The title compound was prepared from 1-[5-Cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carbonyl]-piperidin-4-one (Example 181B) and (R)-1-pyrrolidin-2-yl-methanol in direct analogy to the general procedure used in example 129. MS: 477.3 (MH+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>CC(O)C>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:24][CH3:25])[N:15]=[CH:14][N:13]=[C:12]2[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH:2]1[CH3:1]
Reactant: CC1Cc2ccccc2N1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CC(C)O
Product: COc1cc2ncnc(N3c4ccccc4CC3C)c2cc1OC
Yield: 91 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 91% yield from 2-methyl-indoline (1.1 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 154°-156.5° C.; GC-MS: 321 (M+); anal. RP18-HPLC RT: 4.93 min.).