Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1C(=O)CCC1.[CH3:8][O:9][C:10]1[N:15]=[CH:14][C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][CH:11]=1.CC(C)([O-])C.[K+].[CH3:30][C@:31]1([CH2:39][N:40]2[C:44]3[CH:45]=[C:46]([C:49]#[N:50])[CH:47]=[CH:48][C:43]=3[N:42]=[CH:41]2)CCC[C@:33]2(OC2)[CH2:32]1>CC#N>[CH3:8][O:9][C:10]1[N:15]=[CH:14][C:13]([N:16]2[CH2:21][C@@:19]3([CH2:20][CH2:33][CH2:32][C@@:31]([CH2:39][N:40]4[C:44]5[CH:45]=[C:46]([C:49]#[N:50])[CH:47]=[CH:48][C:43]=5[N:42]=[CH:41]4)([CH3:30])[CH2:22]3)[O:18][C:17]2=[O:23])=[CH:12][CH:11]=1
Reactant: COc1ccc(NC(=O)OC(C)(C)C)cn1
Reactant: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@@]2(CO2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN1CCCC1=O
Product: COc1ccc(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)cn1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 33.6 %

Procedure:
To a 4 mL vial was added NMP (1997 μL), tert-butyl (6-methoxypyridin-3-yl)carbamate (448 mg, 1.997 mmol) and potassium tert-butoxide (213 mg, 1.898 mmol) at RT. After stirring for ˜1 min at RT, 1-{[(3S,5S)-5-methyl-1-oxaspiro[2.5]oct-5-yl]methyl}-1H-benzimidazole-6-carbonitrile (281 mg, 0.999 mmol) was added. The solution was then heated to 55° C. and stirred for 17 h. The resulting solution was cooled to RT, diluted with 2 mL of MeCN, then purified on HPLC: 20-60% MeCN/Water over 14 min, Sunfire C-18 column, 0.1% TFA. Fractions containing product were added to a separatory funnel, diluted with DCM and saturated NaHCO3. DCM layer was separated, passed over a phase separator and concentrated to give 1-(((5S,7S)-3-(6-methoxypyridin-3-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (145 mg, 34% yield). 1H NMR (400 MHz, CDCl3) δ 8.08 (dd, J=4, 12 Hz, 2H), 8.06 (s, 1H), 7.91 (d, J=4 Hz, 1H), 7.76 (s, 1H), 7.58 (dd, J=4 Hz, 1H), 6.80 (d, J=12 Hz, 1H), 4.02 (s, 2H), 3.94 (s, 3H), 3.66 (q, J=8 Hz, 2H), 2.14-2.18 (m, 1H), 1.94-2.00 (m, 2H), 1.66-1.77 (m, 2H), 1.51 (d, J=16 Hz, 1H), 1.36-1.44 (m, 2H), 1.33 (s, 3H). MS (m/z) 432.2 (M+H+).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH:8]([CH3:21])[CH2:9][N:10]2[C:14]([CH2:15][C:16](OCC)=[O:17])=[CH:13][S:12][C:11]=12)=[O:6])([CH3:3])[CH3:2].[CH3:22][NH2:23]>>[CH3:22][NH:23][C:16](=[O:17])[CH2:15][C:14]1[N:10]2[CH2:9][CH:8]([CH3:21])[C:7]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])=[C:11]2[S:12][CH:13]=1
Reactant: CN
Reactant: CCOC(=O)CC1=CSC2=C(C(=O)OC(C)C)C(C)CN12
Product: CNC(=O)CC1=CSC2=C(C(=O)OC(C)C)C(C)CN12
Temperature: 20 °C
Reaction time: 24 h

Procedure:
3.3 g of ethyl (7-isopropoxycarbonyl-6-methyl-5,6-dihydropyrrolo[2,1-b]thiazol-3-yl)acetate was added to 60 ml of a 40% aqueous solution of monomethylamine and stirred at 20° C. for 24 hours. The precipitate was collected by filtration, washed with water, dried, and recrystallized from ethanol. Thus 2.2 g of the title compound was obtained.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]([CH3:46])[CH2:43][CH2:44][CH3:45])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:39][CH2:40][N:42]([CH3:46])[CH2:43][CH2:44][CH3:45])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCCN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCCN(C)CCOc1ccc(CN(CC)c2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 49.2 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-methyl-N-propyl acetamide (8.7 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.4 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:10][OH:11])=[N:4][C:5]([CH2:8][OH:9])=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[CH2:18]([O:1][C:2]1[C:3]([CH2:10][OH:11])=[N:4][C:5]([CH2:8][OH:9])=[CH:6][CH:7]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: OCc1ccc(O)c(CO)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCc1ccc(OCc2ccccc2)c(CO)n1

Procedure:
47 g (0.3 mol) of 3-hydroxy-2,6-bis(hydroxymethyl)pyridine are dissolved in 800 ml of acetonitrile. 104 g of K2CO3 (0.753 mol) and 55 ml of benzyl bromide (0.45 mol) are added. The combined mixture is brought to reflux for 12 h. After having filtered off the insoluble material, the solution is concentrated and the residue is hardened in isopropyl ether. w=39 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:14]2[NH:35][C:17]3=[N:18][C:19]([N:22]4[CH2:27][CH2:26][CH2:25][C@@H:24]([C:28]([N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)=[O:29])[CH2:23]4)=[CH:20][CH:21]=[C:16]3[N:15]=2)[N:13]=1)[C:6]([O:8]CC)=[O:7].[OH-].[Li+]>O1CCCC1.CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:14]2[NH:35][C:17]3=[N:18][C:19]([N:22]4[CH2:27][CH2:26][CH2:25][C@@H:24]([C:28]([N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)=[O:29])[CH2:23]4)=[CH:20][CH:21]=[C:16]3[N:15]=2)[N:13]=1)[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1cc(OC)nc(-c2nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3[nH]2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)O)cc(-c2nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3[nH]2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-ethyl 2-methoxy-6-(5-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)isonicotinate (Example 96, 50 mg, 0.1 mmol) in tetrahydrofuran (1.0 mL) was added a solution of lithium hydroxide (14.9 mg, 0.6 mmol) in methanol (1.0 mL) and water (1.0 mL). The resulting suspension was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. To the residue was added a saturated solution of ammonium chloride in water (10 mL). The pH of the mixture was adjusted to 3 using aqueous hydrochloric acid (1N). The mixture was extracted with ethyl acetate (20 mL×3). The organics were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via HPLC to afford the title compound. MS (ESI+) (M+H) 451.1; HPLC retention time 2.21 min (Method A).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.CCN(C(C)C)C(C)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>C(Cl)Cl>[CH3:24][S:25]([O:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[CH:12][CH:11]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(-c2cnccn2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCc1ccc(-c2cnccn2)cc1
Reaction time: 1 h
Yield: 86 %

Procedure:
To a stirred solution of (4-(pyrazin-2-yl)phenyl)methanol (40 mg, 0.22 mmol) and DIEA (56 μL, 0.32 mmol) in DCM (1 mL) was added methanesulfonyl chloride (29.5 mg, 0.258 mmol) at 0° C. The reaction mixture was stirred at that temperature for 1 h, poured into water, and extracted with DCM. The combined organics were dried and concentrated to give the title compound (50 mg) without further purification. LCMS m/z=265.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:54]([C:57]1[S:58][CH:59]=[C:60]([CH3:62])[CH:61]=1)=[C:55]=[O:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:55]([NH:54][C:57]2[S:58][CH:59]=[C:60]([CH3:62])[CH:61]=2)=[O:56])[CH2:51][CH2:52]1
Reactant: Cc1csc(N=C=O)c1
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1csc(NC(=O)N2CCC(CCOc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)c1
Yield: 34 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 2-isocyanato-4-methylthiophene as the starting materials in 34% yield. LCMS for C30H33ClN7O2S (M+H)+: m/z=590.0.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([NH:7][CH2:8][C:9]([OH:11])=O)=[O:6].CCN=C=NCCCN(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.Cl.[Cl:39][C:40]1[CH:53]=[CH:52][C:43]([CH2:44][N:45]2[CH2:50][CH2:49][CH2:48][CH:47]([NH2:51])[CH2:46]2)=[CH:42][CH:41]=1>C(Cl)(Cl)Cl.CCN(CC)CC>[Cl:39][C:40]1[CH:41]=[CH:42][C:43]([CH2:44][N:45]2[CH2:50][CH2:49][CH2:48][CH:47]([NH:51][C:9](=[O:11])[CH2:8][NH:7][C:5](=[O:6])[C:4]3[CH:12]=[CH:13][CH:14]=[C:2]([CH3:1])[CH:3]=3)[CH2:46]2)=[CH:52][CH:53]=1
Reactant: NC1CCCN(Cc2ccc(Cl)cc2)C1
Reactant: Cc1cccc(C(=O)NCC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C(=O)NCC(=O)NC2CCCN(Cc3ccc(Cl)cc3)C2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-(3-Methylbenzoyl)glycine (10.6 mg, 0.055 mmol), EDCI (10.5 mg) and 1-hydroxybenzotriazole hydrate (7.4 mg) were added to a solution of 1-(4-chlorobenzyl)-3-aminopiperidine dihydrochloride (14.9 mg, 0.050 mmol) and Et3N (15.2 mg) in CHCl3 (2.5 mL). The reaction mixture was stirred at 25° C. for 16 h, washed with 2 N aqueous NaOH (2 mL×2) and brine (1 mL). After filtration through PTFE membrane filter, the solvent was removed under reduced pressure to afford 1-(4-chlorobenzyl)-3-[{N-(3-methylbenzoyl)glycyl}amino]piperidine (compound No. 355) as a pale yellow oil (17.4 mg, 87%): The purity was determined by RPLC/MS (97%); ESI/MS m/e 400.0 (M++H, C22H26ClN3O2).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].O[C:6]1[CH:19]=[CH:18][C:9]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:8][CH:7]=1>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.CC1C=CC=CC=1C>[Cl:4][C:1]([C:15]1[CH:16]=[CH:17][C:12]([C:10]([C:9]2[CH:18]=[CH:19][CH:6]=[CH:7][CH:8]=2)=[O:11])=[CH:13][CH:14]=1)=[O:2]
Reactant: O=C(Cl)Cl
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
A total of 3.4 kg of phosgene were passed in the course of 5 hours into a solution of 4 kg of 4-hydroxybenzophenone and 190 g of benzyltrimethylammonium chloride in 11.4 kg of o-xylene. During this time, the internal temperature was increased from 95° to 1200° C. After the end of the introduction of phosgene, stirring was continued for 30 minutes at 115° C. Working up was carried out by expelling the excess phosgene with nitrogen. The salt (catalyst) precipitated toward the end of the reaction was filtered off and the solvent was distilled off. 4.9 kg (93%) of yellowish 4-chloroformylbenzophenone of melting point 67°-72° C. were obtained. This crude product containing 12.69% of Cl- (theoretical value 13.60%) was used directly for the subsequent reactions, without further purification.
Reaction SMILES: O=[CH:2][C@@H:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[C:22](=O)([O-])[O-].[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO.CCOC(C)=O>[CH2:5]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:4][C@H:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:2]#[CH:22]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#C[C@H](CCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 15 h
Yield: 65 %

Procedure:
To a solution of (S)-di-tert-butyl (4-oxobutane-1,3-diyl)dicarbamate (1.47 g, 4.86 mmol) in MeOH (30 mL) was added potassium carbonate (1.680 g, 12.15 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (1.40 mL, 7.29 mmol), sequentially. After stirring for 15 h, the mixture was diluted with EtOAc, washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified via silica gel chromatography (EtOAc-Heptane) to afford the title compound (0.943 g, 65%). LCMS: Rt=0.81 min, m/z=321.1 (M+Na) Method 2m_acidic.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:16]=[C:17]([NH2:33])[N:18](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[CH3:15].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]([NH2:33])=[NH:18])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[CH3:15]
Reactant: Cc1cc(N=C(N)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc1N1C[C@@H]2C[C@H]1CN2C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(NC(=N)N)ccc1N1C[C@@H]2C[C@H]1CN2C

Procedure:
A solution of [3-methyl-4-((1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptan-5-yl)phenyl][N,N-bis(tert-butoxycarbonyl)]guanidine (0.100 g) in CH2Cl2 (20 mL) with TFA (5 mL) was stirred at ambient temperature for 4 h. The reaction progress was monitored by TLC (silica gel). The resulting mixture was concentrated and the lyophilized to afford [3-methyl-4-((1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptan-5-yl)phenyl]guanidine, as a TFA salt; LCMS: purity: 89%; MS (m/e): 260 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:20](=O)[CH2:21][CH3:22])C.CS(O)(=O)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)=[C:20]([CH2:21][CH3:22])[NH:13]2
Reactant: CCOC(=O)C(Cc1ccc(Cl)cc1)C(=O)CC
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CCc1[nH]c2c(Cl)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of (3-amino-4-chlorophenoxy)acetic acid methyl ester (0.53 g), 2-(4-chlorobenzyl)-3-oxopentanoic acid ethyl ester (0.66 g), methanesulfonic acid (0.032 mL) and toluene (20 mL) was heated at reflux for 20 hours. The mixture was cooled to room temperature and the solvent removed under reduced pressure. The residue was diluted with water, extracted with ethyl acetate and the combined extracts dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (9:1 by volume) to afford title compound, 0.034 g
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:21][CH3:22])[C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[NH2:33][C@@H:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][C@@H:35]1[OH:43]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:21][CH3:22])[C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:33][C@@H:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][C@@H:35]1[OH:43])=[O:31]
Reactant: COc1ccc(CC2NCCc3c2cc(OC)c(OC)c3OC)cc1OC
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: O=C(Br)CBr
Product: COc1ccc(CC2c3cc(OC)c(OC)c(OC)c3CCN2CC(=O)N[C@@H]2c3ccccc3C[C@@H]2O)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with (1R,2S)-1-amino-2-indanol
Reaction SMILES: C(OC([NH:8][C@H:9]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:14][N:13]([CH2:25][C:26]2[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:29]=[CH:28][C:27]=2[F:36])[C:12]1=[O:37])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@H:9]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:14][N:13]([CH2:25][C:26]2[C:31]([C:32]([F:34])([F:33])[F:35])=[CH:30][CH:29]=[CH:28][C:27]=2[F:36])[C:12]1=[O:37]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(-c2ccccc2Cl)cn(Cc2c(F)cccc2C(F)(F)F)c1=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cn1c(=O)c(-c2ccccc2Cl)cn(Cc2c(F)cccc2C(F)(F)F)c1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.7 %

Procedure:
To a solution of compound 6e (0.144 g, 0.23 mmol) in DCM (1 mL) was added TFA (0.5 mL, 6.5 mmol) and the mixture was stirred at room temperature for 1.5 hours. After concentration, the residue was taken up in DCM and sat'd aq. NaHCO3 was added. The aqueous layer was extracted with DCM. Combined organic extracts were dried over Na2SO4 and concentrated to give compound 6f (0.12 g). MS (CI) m/z 518.0, 520.1 (MH+).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[O:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[CH2:22][C@H:23]4[C@@H:28]([C:29]=3[CH:30]=2)[CH2:27][CH2:26][CH2:25][NH:24]4)=[CH:14]1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:24]3[CH2:25][CH2:26][CH2:27][C@@H:28]4[C:29]5[CH:30]=[C:18]([C:15]6[CH:16]=[CH:17][O:13][CH:14]=6)[CH:19]=[CH:20][C:21]=5[CH2:22][C@H:23]34)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1cc(-c2ccc3c(c2)[C@H]2CCCN[C@H]2C3)co1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@@H]2c3cc(-c4ccoc4)ccc3C[C@@H]21
Yield: 14 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-6-furan-3-yl-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1. Yield: 14% of theory; LC (method 1): tR=2.89 min; Mass spectrum (ESI+): m/z=384 [M+H]+.
Reaction SMILES: Br[C:2]([F:25])([F:24])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[C:4]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[F-:26].[K+].CC#N>O>[CH3:17][S:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[C:4]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:3]([C:2]([F:25])([F:26])[F:24])[O:7][N:6]=2)=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)c1ccc(-c2noc(C(F)(F)Br)c2-c2ccccc2)cc1
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2noc(C(F)(F)F)c2-c2ccccc2)cc1
Reaction time: 0.39 h
Yield: 48.2 %

Procedure:
A mixture of 7 (5.4 mg, 0.013 mmol), anhydrous KF (1.1 mg, 0.019 mmol), Kryptofix® 222 (7.0 mg, 0.019 mmol) and dry MeCN (1.0 mL) was refluxed for 50 min. The reaction mixture was diluted with H2O (5 mL) and passed through a Waters Sep-Pak® C-18 cartridge (1 mL). The cartridge was washed with H2O (3×3 mL) and with MeCN (3 mL). The MeCN eluate was purified by semi-preparative HPLC (Phenomenex® HPLC column: aqua, 5μ, C-18, 10 mm×250 mm) with MeCN—H2O (3:1) containing 0.075% TFA (5 mL/min). The fractions at 22-25 min were combined and concentrated to yield 8 (2.3 mg, 50%) as a colorless solid. The 1H NMR spectrum was identical with those reported (Habeeb, A. G.; Rao, P. N. P.; Knaus, E. E. Drug Dev. Res. 2000, 51, 273-286).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:13][CH2:12][C@H:11]([NH:14]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(O)C=CC=CC=1.Br>C(O)(=O)C>[NH2:14][C@H:11]1[CH2:12][CH2:13][N:9]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:10]1
Reactant: Cc1ccc(S(=O)(=O)N[C@H]2CCN(Cc3ccccc3)C2)cc1
Agent: Br
Agent: Cl
Solvent: Oc1ccccc1
Solvent: CC(=O)O
Product: N[C@H]1CCN(Cc2ccccc2)C1

Procedure:
(S)-1-Benzyl-3-(p-toluenesulfonylamino)pyrrolidine hydrochloride (40.0 g), phenol (12.0 g) and 30% hydrogen bromide in acetic acid (200 mL) were combined and heated in a sealed flask at 105° C. to 125° C. for a period of 55 minutes. The resulting red solution was concentrated under vacuum to remove excess acetic acid and hydrogen bromide and the thick oil dissolved in water (500 mL) and toluene (150 mL). The layers were separated and the aqueous layer extracted with toluene (50 mL) and diethyl ether (30 mL) and treated with 28% ammonium hydroxide (11 mL) to give a pH of 8.5. This solution was extracted with toluene (25 mL) and all of the organic extracts discarded. The remaining aqueous layer was treated with 50% NaOH (145 mL) and extracted with toluene (3×50 mL). The combined toluene extracts were concentrated to an oil (19.2 g) which was distilled under vacuum (bp 104°-106° C. at 2.5 mm Hg) to give (S)-3-amino-1-benzylpyrrolidine, 5, (18.2 g, 94%) as a colorless oil: [α]25 =+11.2°.
Reaction SMILES: [OH:1][CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][CH:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:7][CH:6]=1.CS(C)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(N(CC)CC)C>C(Cl)Cl>[O:1]=[C:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][CH:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:7][CH:6]=1
Reactant: O=C1NC(=O)C(Cc2ccc(OCC(O)c3ccccc3)cc2)S1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1NC(=O)C(Cc2ccc(OCC(=O)c3ccccc3)cc2)S1
Temperature: 0 °C
Reaction time: 2 h
Yield: 40.3 %

Procedure:
To a stirring solution of 5-[4-(2-hydroxy-2-phenylethoxy)benzyl]-1,3-thiazolidine-2,4-dione (1.00 g, 2.91 mmol) in DCM (35 ml) was added DMSO (2 ml) and the solution was cooled to 0° C. Phosphorus pentoxide (0.83 g, 2.91 mmol) was added followed by triethylamine (1.8 mL, 13.1 mmol). The reaction was allowed to slowly warm to RT. After 2 hours, the reaction mixture was partitioned between DCM and water and the organic phase was washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting yellow oil was chromatographed on silica gel eluting with 25-35% EtOAc/hexanes. Fractions containing product were combined and evaporated in vacuo to give 0.40 g (40%) of the title compound as a white solid. Trituration with ether afforded 245 mg of clean product. MS (ESI−) for C18H15NO4S m/z 340.1 (M−H)−
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:36]=[CH:35][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:14](=[O:34])[N:15]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[C:16]([CH3:23])=[C:17]([C:19](=O)[CH2:20]Br)[CH:18]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:37][C:38]([NH2:40])=[S:39].CC([O-])=O.[Na+]>CCO>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:14](=[O:34])[N:15]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=3)[C:16]([CH3:23])=[C:17]([C:19]3[N:37]=[C:38]([NH2:40])[S:39][CH:20]=3)[CH:18]=2)=[O:12])=[CH:35][CH:36]=1)(=[O:3])=[O:4]
Reactant: Cc1c(C(=O)CBr)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(-c2csc(N)n2)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 90 °C
Yield: 69 %

Procedure:
5-Bromoacetyl-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide (Example 50 (c), 0.04 g, 0.067 mmol), thiourea (0.0067 g, 0.086 mmol), NaOAc (0.011 g, 0.136 mmol), EtOH (2 ml) and a magnetic stirrer bar were placed in a tube designed for microwave synthesis. The vial was sealed and the mixture was heated in a CEM Discover Microwave apparatus (100 W, 90° C.) for 20 minutes, giving complete conversion of the starting material to a single product according to LC-MS. The solvents were evaporated to give a crude mixture which was purified on preparative HPLC giving the title compound (0.026 g, 66%) as a slightly yellowish solid after freeze-drying the pure fractions.