Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].O.[Li+].[I-]>N1C=CC=CC=1>[C:17]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[NH:1][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2ccc(Cl)cc21
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Temperature: 120 °C
Reaction time: 72 h
Yield: 29.2 %

Procedure:
To a solution of ethyl 3-amino-2-benzoyl-6-chloro-1H-indole-1-carboxylate (step 2 of Example 1, 200 mg, 0.58 mmol) in pyridine (5 ml) was added methanesufonyl chloride (0.07 ml, 0.87 mmol). After stirring for 72 h, the mixture was poured into water (100 ml) and extracted with diethyl ether (100 ml). The organic extract was washed consecutively with 10% aqueous citric acid (50 ml), water (50 ml), saturated aqueous sodium bicarbonate (50 ml), water (50 ml) and brine (50 ml), and dried (MgSO4). After removal of solvent the residue (287 mg) was dissolved in DMF (5 ml) and LiI (362 mg, 2.7 mmol) was added. The mixture was heated at 120° C. for 5 h, cooled and partitioned between water (100 ml) and diethyl ether (100 ml). The organic layer was separated and washed with water (100 ml), brine (100 ml) and dried (MgSO4). After removal of solvent the residue was purified by flash chromatography eluting with ethyl acetate/hexane (1:4) to afford the title compound (59 mg, 29%) as a yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[Cl:29][C:30]1[CH:31]=[C:32]([NH2:38])[CH:33]=[C:34]([Cl:37])[C:35]=1[F:36]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:10](=[O:12])[NH:38][C:32]1[CH:31]=[C:30]([Cl:29])[C:35]([F:36])=[C:34]([Cl:37])[CH:33]=1)[CH3:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1cc(Cl)c(F)c(Cl)c1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cc(Cl)c(F)c(Cl)c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−20° C.) solution of (R)-2-tert-butoxycarbonylamino-propionic acid (57.2 g, 302 mmol) in anhydrous THF (582 mL) was added N-methyl-morpholine (34.9 mL, 317 mmol) at a rate to keep the internal temperature at −15° C. Isobutyl chloroformate (42.0 mL, 317 mmol) was then added over a 20 min period and the resulting mixture was stirred for 30 min. A solution of 3,5-dichloro-4-fluoro-phenylamine (54.4 g, 302 mmol) in THF (160 mL) was then added over 40 min. The reaction mixture was warmed to 20° C. and stirred for 20 h. The reaction mixture was filtered and concentrated in vacuo. To the resulting oil was added MeOH (200 mL) and the solution was concentrated to provide the title compound as a tan colored solid, m/z 295.3 [M-t-Bu]+. This material was used without further purification.
Reaction SMILES: [C:1]1([C:7]2([CH2:13]OS(C)(=O)=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:19]#[N:20].[Na+]>CS(C)=O.O>[C:1]1([C:7]2([CH2:13][C:19]#[N:20])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)OCC1(c2ccccc2)CCCCC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCC1(c2ccccc2)CCCCC1
Temperature: 140 °C
Reaction time: 16 h
Yield: 16.2 %

Procedure:
To a stirred solution of methanesulfonic acid 1-phenyl-cyclohexylmethyl ester (252) (20.0 g, 74.52 mmol) in dimethyl sulfoxide (100.0 mL) were added KI (1.24 g, 7.45 mmol) and NaCN (5.48 g, 111.78 mmol) and the reaction mixture was stirred at 140° C. for 16 h. After completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate and the organic layer was washed with water and brine. The organic layer was then dried over Na2SO4 and concentrated. The crude product was purified by normal silica gel column chromatography (using 5% ethyl acetate in hexane) to get (1-phenyl-cyclohexyl)-acetonitrile (253) (2.4 g, 16.1%) as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C@@H:5]([NH2:20])[C:6]1[CH:11]=[CH:10][C:9]([NH:12]C(OC(C)(C)C)=O)=[CH:8][CH:7]=1.[C:22](OC)(=[O:29])[CH2:23][CH2:24][CH2:25][C:26]([O-:28])=[O:27].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C@@H:5]([NH:20][C:22](=[O:29])[CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=1
Reactant: COC(=O)CCCC(=O)[O-]
Reactant: COC(=O)C[C@@H](N)c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H](NC(=O)CCCC(=O)O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (R)-3-amino-3-[4-(tert-butoxycarbonylamino)phenyl]-propanoic acid methyl ester [1.5 g, Reference Example 7(c)], mono-methyl glutarate (0.7 ml), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (2.05 g), diisopropylethylamine (1.8 ml) and dimethylformamide (40 ml) was stirred at ambient temperature for 18 hours. The reaction mixture was evaporated to dryness and diluted with water (75 ml) and the resultant mixture acidified to pH1.0 by addition of concentrated hydrochloric acid. The mixture was extracted twice with ethyl acetate (75 ml). The combined extracts were washed with water (75 ml) then dried over magnesium sulphate and then evaporated. The resulting waxy fawn solid (3.8 g) was dissolved in dichloromethane (20 ml), cooled to 0° C., and the solution treated with trifluoracetic acid (4 ml). After stirring at ambient temperature for 2 hours the reaction mixture was evaporated and the residue taken up in ethyl acetate (50 m). The resultant solution was treated with ice cold saturated aqueous potassium carbonate solution (20 ml) with stirring at ambient temperature for 5 minutes. The organic layer was separated, washed with water (30 ml), dried over magnesium sulphate, and then evaporated to give (R)3-(4-carboxybutanoyl-amino)-3-(4-aminophenyl)-propanoic acid methyl ester (1.32 g) as a yellow oil.
Reaction SMILES: [C:1]1([C:7]([NH2:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[CH2:22][CH3:23]>C(#N)C>[C:1]1([C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:20][CH2:22][CH3:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCI
Solvent: CC#N
Product: CCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 72 h
Yield: 27.9 %

Procedure:
Triphenylmethylamine (1.00 g, 3.86 mmol) (Wako Pure Chemical Industries, Ltd.) and iodoethane (1.50 g, 9.62 mmol) (Wako Pure Chemical Industries, Ltd.) were dissolved in acetonitrile (5 mL) (Wako Pure Chemical Industries, Ltd.), and the mixture was left to stand still at room temperature for 3 days. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform (Wako Pure Chemical Industries, Ltd.) as an eluent), to thereby obtain the title compound (0.31 g, 28% yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:35][C@H:34]([CH2:36][O:37]C(=O)C4C=CC=CC=4)[C@@H:23]([O:24]C(=O)C4C=CC=CC=4C)[C@H:13]3[O:14]C(=O)C3C=CC=CC=3)[C:6]=2[N:7]=1.[C:46]([O-])([O-])=O.[K+].[K+].CC(O)=O>CO>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:35][C@H:34]([CH2:36][OH:37])[C@@H:23]([OH:24])[C@@:13]3([CH3:46])[OH:14])[C:6]=2[N:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccccc1C(=O)O[C@H]1[C@@H](OC(=O)c2ccccc2)[C@H](n2c(=O)sc3cnc(N)nc32)O[C@@H]1COC(=O)c1ccccc1
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1c(=O)sc2cnc(N)nc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 53 %

Procedure:
To a suspension of nucleoside 3 (380 mg, 0.606 mmol) in MeOH (20 mL) was added K2CO3 (17 mg, 0.12 mmol) at rt. The resulting mixture was stirred 18 h at rt whereupon it was treated with HOAc (15 μL, 0.25 mmol), concentrated and submitted to HPLC purification (MeCN—H2O), affording 20 mg (10%) of the title compound 4 as a white solid after lyophilization: 1H (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 6.86 (br s, 2H), 6.09 (br s, 1H), 5.19 (br s, 1H), 4.88 (br s, 1H), 4.55 (t, J=5.87, 1H), 3.97 (br s, 1H), 3.76-3.81 (m, 1H), 3.61 (br s, 2H), 1.04 (s, 3H); [M+H]+ m/z 315. Analysis calc'd for C11H14N4O5S.H2O: C, 39.75; H, 4.85; N, 16.86; S, 9.65. Found: C, 40.23; H, 4.76; N, 16.64; S, 9.45.
Reaction SMILES: [CH:1]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C(N(C(C)C)CC)(C)C.Br[CH2:36][CH2:37][CH2:38][OH:39]>C(O)CCC>[CH:1]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:36][CH2:37][CH2:38][OH:39])[CH2:16][CH2:15]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCCBr
Reactant: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: OCCCN1CCC(C(c2ccccc2)c2ccccc2)CC1

Procedure:
4-Benzhydrylpiperidine (10 mmol, 2.87 g) is slurried in n-butanol (30 mL), and K2CO3 (s) (2.76 g, 10 mmol) or diisopropylethylamine (20 mmol, 2.5 g) and 3-bromopropanol (10 mmol, 1.39 g) are added to the slurry. The stirred mixture is refluxed for about 7 hours under N2 (g), filtered, and concentrated in vacuo. The residue is dissolved in hot CHCl3, filtered and concentrated in vacuo to yield crude product as an oil (3.0-3.1 g) which is used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:13]([CH2:24][CH3:25])[C:14]3[C:19]([C:20]=2[C:21]#[N:22])=[CH:18][CH:17]=[C:16]([OH:23])[CH:15]=3)[CH:7]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:34][CH2:35][CH2:36]Cl.O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:26])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:13]([CH2:24][CH3:25])[C:14]3[C:19]([C:20]=2[C:21]#[N:22])=[CH:18][CH:17]=[C:16]([O:23][CH2:34][CH2:35][CH2:36][N:13]2[CH2:14][CH2:19][CH2:20][CH2:12]2)[CH:15]=3)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Nc1cccc(-c2c(C#N)c3ccc(O)cc3n2CC)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Nc1cccc(-c2c(C#N)c3ccc(OCCCN4CCCC4)cc3n2CC)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 164.1 %

Procedure:
To a solution of [3-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid ethyl ester (1.2 g, 2.91 mmol) in DMF (10 mL) is added K2CO3 (538 mg, 3.9 mmol) and 3-bromo-1-chloropropane (383 uL, 3.9 mmol) and the reaction is stirred for overnight at 50° C. The reaction mixture is then poured into cold water and the precipitate is collected by filtration and washed with hexane and dried in vacuo to afford 1.1 g, 89% of the desired product.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([NH:13][C:14](=[O:16])[CH3:15])[N:7]=1.[OH-].[Na+]>CO.O>[C:14]([NH:13][C:8]1[N:7]=[C:6]([CH2:5][CH2:4][C:3]([OH:17])=[O:2])[CH:11]=[C:10]([CH3:12])[CH:9]=1)(=[O:16])[CH3:15]
Reactant: COC(=O)CCc1cc(C)cc(NC(C)=O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)Nc1cc(C)cc(CCC(=O)O)n1
Reaction time: 18 h
Yield: 92 %

Procedure:
6.15 g of 3-(6-acetylamino-4-methyl-pyridin-2-yl)-propionic acid methyl ester (compound C5) is dissolved in 100 ml methanol and 70 ml water. Subsequently, 30.44 ml of a 1.0 M solution of NaOH is added while stirring is continued for 18 h at r.t. 2.0 g of amberlite IR-120 [H+] is added and the suspension is stirred for 10 min to neutralize the reaction mixture. The ion exchange resin is removed by filtration and 7.1 g of the crude product is isolated as a colourless solid after evaporation of solvent. Purification by chromatography on silica gel (eluent: dichloromethane/ethanol 10:1) affords 5.32 g of the title compound. M.p. 202° C. ESI-MS: 223.1 (MH+). TLC: Rf=0.13 (cyclohexane/ethyl acetate 1:1+1.0 vol % acetic acid).
Reaction SMILES: [OH:1][CH:2]1[C:18]([CH3:20])([CH3:19])[C:17](=[O:21])[CH:16]([CH3:22])[CH:15]([OH:23])[CH:14]([CH3:24])[CH2:13][CH2:12][CH2:11][CH:10]2[CH:8]([N:9]2[CH2:25][CH2:26][OH:27])[CH2:7][CH:6]([C:28]([CH3:36])=[CH:29][C:30]2[N:31]=[C:32]([CH3:35])[S:33][CH:34]=2)[O:5][C:4](=[O:37])[CH2:3]1.[C:38](=O)([O-:59])[O:39][CH2:40][CH:41](N1C2C=CC=CC=2N=N1)[S:42][S:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1>ClCCl.CN(C1C=CN=CC=1)C>[C:38](=[O:59])([O:39][CH2:40][CH2:41][S:42][S:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1)[O:27][CH2:26][CH2:25][N:9]1[C@@H:8]2[C@H:10]1[CH2:11][CH2:12][CH2:13][C@H:14]([CH3:24])[C@H:15]([OH:23])[C@@H:16]([CH3:22])[C:17](=[O:21])[C:18]([CH3:19])([CH3:20])[C@@H:2]([OH:1])[CH2:3][C:4](=[O:37])[O:5][C@H:6](/[C:28](/[CH3:36])=[CH:29]/[C:30]1[N:31]=[C:32]([CH3:35])[S:33][CH:34]=1)[CH2:7]2
Reactant: O=C([O-])OCC(SSc1ccccn1)n1nnc2ccccc21
Reactant: CC(=Cc1csc(C)n1)C1CC2C(CCCC(C)C(O)C(C)C(=O)C(C)(C)C(O)CC(=O)O1)N2CCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C/C(=C\c1csc(C)n1)[C@@H]1C[C@H]2[C@@H](CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)N2CCOC(=O)OCCSSc1ccccn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-17-[2-hydroxyethyl]-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-oxa-17-azabicyclo[14.1.0]heptadecane-5,9-dione in anhydrous dichloromethane at 0° C. was added DMAP (1.2 eq.) and benzo[d][1,2,3]triazol-1-yl2-(2-(pyridin-2-yl)disulfanyl)ethyl carbonate (1.0 eq.) in tandem. The reaction mixture was stirred at 0° C. under argon and monitored by TLC every 10 min. Additional DMAP (1.2 eq.) and Compound I (2)(1.0 eq.) were added as necessary until all of Compound G was consumed. The reaction was quenched with MeOH (1 mL) at 0° C., the solvent was removed under vacuum, and the residue was purified by chromatography (silica gel, 2.5-5% MeOH in DCM) to afford the title compound as a beige solid. Compound amounts and recoveries are listed below in Table 2. Total yield from 2.95 g of Compound G was 2.80 g (67.9%) of Compound I.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][C:26](=[O:28])[CH3:27])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Cl:36])C(=O)C1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][C:26](=[O:28])[CH3:27])=[C:8]2[C:16]([Cl:36])=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccccc2F)c1OC(C)=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2Cc2ccccc2F)c1OC(C)=O

Procedure:
Prepared in analogy to that of Example 124(b) from 4-acetoxy-7-cyano-1-(2-fluoro-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and NCS in MeCN. The title compound, ESI MS (m/z): 416 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:9]1([C:14](=O)[CH2:15][CH2:16][C:17](=O)[CH3:18])[CH2:13][CH2:12][CH2:11][CH2:10]1.C(=O)(O)[O-].[Na+]>ClCCl.O>[CH:9]1([C:14]2[N:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:17]([CH3:18])=[CH:16][CH:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(=O)CN
Reactant: CC(=O)CCC(=O)C1CCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Cn1c(C)ccc1C1CCCC1
Yield: 72.5 %

Procedure:
A slurry of ethyl 2-aminoacetate hydrochloride (2.93 g, 21.0 mmol), 1-cyclopentylpentane-1,4-dione (3.43 g, 20.4 mmol), and sodium bicarbonate (4.28 g, 51.0 mmol) in dichloromethane (20.4 mL) was heated at 50° C. for 72 hours, after which the reaction was diluted in water and extracted with dichloromethane (3×30 mL), dried (sodium sulfate), filtered and concentrated to a gold residue. Purification by silica gel chromatography (ISCO 120 g, 20 mL/min) using 0 to 35% ethyl acetate in hexanes afforded ethyl 2-(2-cyclopentyl-5-methyl-1H-pyrrol-1-yl)acetate (3.49 g, 14.8 mmol, 73% yield) as a clear colorless liquid. 1H NMR (400 MHz, CDCl3) δ (ppm): 5.84 (s, 2H, two shifts isochronous), 4.54 (s, 2H), 4.23 (q, 2H), 2.83 (m, 1H), 2.19 (s, 3H), 1.91-1.98 (m, 2H), 1.73-1.79 (m, 2H), 1.58-1.64 (m, 4H), 1.27 (t, 3H).
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1>C(OCC)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:7]2([OH:10])[CH2:6][CH2:5][C:4]3([O:3][CH2:2][CH2:1][O:11]3)[CH2:9][CH2:8]2)=[CH:15][CH:14]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: CCOCC
Product: OC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 94.1 %

Procedure:
To a solution of 1,4-cyclohexanedione mono-ethylene ketal (25 g, 0.16 mol) in diethylether (750 ml), cooled to -78° C. was added 4-fluorophenyl magnesium bromide (1 M in tetrahydrofuran, 190 ml, 0.19 mol) dropwise. The reaction mixture was warmed to room temperature, quenched with water and extracted twice with ethyl acetate. Washing with brine, drying and solvent evaporation gave 8-(4-fluorophenyl)-1,4-dioxa-spiro[4.5]decan-8-ol (38 g, 95%).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:16]=1[N:24]=[C:25]=[O:26])([CH3:14])[CH3:13].N1C=CC=CC=1>ClCCl>[CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:22])[CH3:23])[C:16]=1[NH:24][C:25]([NH:11][CH:8]1[CH2:7][CH2:6][CH:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][CH2:9]1)=[O:26])([CH3:13])[CH3:14]
Reactant: CC(C)(C)C1CCC(N)CC1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NC1CCC(C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.5 %

Procedure:
To a solution of 1.6 g of 4-tert-butylcyclohexylamine in 15 ml of dichloromethane was added a solution of 2.2 g of 2,6-diisopropylphenylisocyanate in dichloromethane dropwise in the presence of pyridine at 0° C. Thereafter the mixture was stirred for 1.5 hours at room temperature and concentrated. The residue was partitioned between isopropyl ether and water, and the organic layer was successively washed with 0.5N hydrochloric acid, water and sodium sulfate solution. The organic layer was dried over magnesium sulfate and then distilled away. The resulting residue was crystallized from ethyl acetate to give 2.2 g of N-(2,6-diisopropylphenyl)-N'-(4-tert-butylcyclohexyl)urea, melting at 270° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14](=O)[NH:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)=O)[CH:12]2[CH2:27][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.C([O-])(=O)C.[NH4+:36]>C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]2[NH:36][C:17]([C:19]3[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=3)=[CH:16][N:15]=2)[CH:12]2[CH2:27][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)NCC(=O)c1ccc(Br)cc1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(Br)cc2)[nH]1
Yield: 72.3 %

Procedure:
The mixture of 3-[2-(4-bromo-phenyl)-2-oxo-ethylcarbarnoyl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.7 g, 4 mmol), acetic acid (24 up, and ammonium acetate (1.54 g, 20 mmol) in xylene (20 ml) was heated at 140° C. for 20 hours. The mixture was quenched with saturated sodium carbonate solution, and extracted with EtOAc. The organic phase was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave 3-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.21 g). m/z: 417.9 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:13]([CH3:14])=[CH:12][C:5]([O:6][C@@H:7]2[CH2:11][CH2:10][O:9][CH2:8]2)=[CH:4][C:3]=1[CH2:15]Br.[C:17]([O-:20])(=[O:19])[CH3:18].[K+].O>CN(C)C=O>[C:17]([O:20][CH2:15][C:3]1[CH:4]=[C:5]([O:6][C@@H:7]2[CH2:11][CH2:10][O:9][CH2:8]2)[CH:12]=[C:13]([CH3:14])[C:2]=1[Br:1])(=[O:19])[CH3:18]
Reactant: Cc1cc(O[C@@H]2CCOC2)cc(CBr)c1Br
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc(O[C@@H]2CCOC2)cc(C)c1Br
Temperature: 50 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
(R)-3-(4-Bromo-3-(bromomethyl)-5-methylphenoxy)tetrahydrofuran 35b (700 mg, 2 mmol) was dissolved in 15 mL of N,N-dimethylformamide, followed by addition of potassium acetate (197 mg, 2 mmol). The reaction solution was heated to 50° C. and stirred for 1 hour. The resulting solution was cooled down to room temperature, mixed with 100 mL of water and extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (R)-2-bromo-3-methyl-5-((tetrahydrofuran-3-yl)oxy)benzyl acetate 35c (658 mg) as a yellow oil, which was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH:4]([CH2:9][C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1.[NH2:18][C:19]1[CH:20]=[C:21]([C:25]([OH:27])=[O:26])[CH:22]=[N:23][CH:24]=1>>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5]2[N:18]([C:19]3[CH:20]=[C:21]([C:25]([OH:27])=[O:26])[CH:22]=[N:23][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][C:4]=2[CH2:3]1
Reactant: Nc1cncc(C(=O)O)c1
Reactant: CC1CCC(=O)C(CC(=O)c2ccccc2)C1
Product: CC1CCc2c(cc(-c3ccccc3)n2-c2cncc(C(=O)O)c2)C1
Yield: 48 %

Procedure:
Following the general methods as outlined under Intermediate 13, starting from 4-methyl-2-(2-oxo-2-phenylethyl)cyclohexanone and 5-aminopyridine-3-carboxylic acid, the title compound was isolated in 48% yield (98% purity by HPLC). MS(ESI+): 334.5; MS(ESI−): 332.4.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Br:8].[Na].[CH:10]([OH:13])([CH3:12])[CH3:11]>>[Br:8][CH:7]([O:13][CH:10]([CH3:12])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH3:2]
Reactant: CC(C)O
Reactant: BrCCCCCCBr
Agent: [Na]
Product: CCCCCC(Br)OC(C)C

Procedure:
The above compound is produced in analogy to Example 10, using isopropanol and 1,6-dibromohexane and sodium instead of sodium hydride. B.P.: 96°-98°/15 mm Hg.
Reaction SMILES: [Cl:1]C1C=CC=C(C(OO)=[O:9])C=1.[NH:12]=[C:13]1[N:17]([CH2:18][CH2:19][S:20][CH2:21][CH2:22][CH3:23])[C:16]2[CH:24]=[CH:25][C:26]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:27][C:15]=2[S:14]1.C(OCC)C.Cl>C(O)C>[ClH:1].[NH:12]=[C:13]1[N:17]([CH2:18][CH2:19][S:20]([CH2:21][CH2:22][CH3:23])=[O:9])[C:16]2[CH:24]=[CH:25][C:26]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:27][C:15]=2[S:14]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCSCCn1c(=N)sc2cc(OC(F)(F)F)ccc21
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCCS(=O)CCn1c(=N)sc2cc(OC(F)(F)F)ccc21
Temperature: -35 °C
Reaction time: 0.17 h
Yield: 38.8 %

Procedure:
70-75% pure m-chloroperbenzoic acid (4.3 g) is added in the course of approximately 10 minutes to 2-imino-3-(2-propylthioethyl)-6-trifluoromethoxybenzothiazoline (5.87 g) dissolved in absolute ethanol (80 cc) cooled to -35° C. The reaction is continued for 10 minutes at the same temperature. The reaction medium is then added to ethyl ether (300 cc) and treated with 4.2N ethereal hydrogen chloride (4.2 cc). The precipitate formed is filtered off, then taken up in distilled water (50 cc) and neutralized with 1N sodium hydroxide. After extraction with ethyl acetate, drying over magnesium sulphate and concentration to dryness under reduced pressure (20 mm Hg; 2.7 kPa), the crude product is purified by chromatography on a silica column, with ethyl acetate and then a mixture of ethyl acetate and methanol (90:10 by volume) as eluents. After conversion to hydrochlorides, 2-imino-3-(2-propylsulphonylethyl)-6-trifluoromethoxybenzothiazoline hydrochloride (0.33 g), subliming at about 200° C., and (RS)-2-imino-3-(2-propylsulphinylethyl)-6-trifluoromethoxybenzothiazoline hydrochloride (2.63 g), m.p. 125° C., are obtained.