Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[C:26]1(=[O:41])[N:30]([CH2:31][CH2:32][CH2:33][CH2:34]Br)[C:29](=[O:36])[C:28]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:27]12>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:34][CH2:33][CH2:32][CH2:31][N:30]2[C:26](=[O:41])[C:27]3=[CH:40][CH:39]=[CH:38][CH:37]=[C:28]3[C:29]2=[O:36])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCCCCN2C(=O)c3ccccc3C2=O)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
6-Amino-9-benzyl-8-hydroxy-2-mercaptopurine (120 mg, 0.44 mmol) was suspended in dimethylformamide (10 ml). To the suspension were added potassium carbonate (60 mg, 0.43 mmol) and 4-phthalimidobutyl bromide (113 mg, 0.40 mmol) in order. The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo, and water and methanol were added to the residue, and the resulting crystals were taken by filtration to give the subject compound (141 mg, yield 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:11]([CH2:20][NH:21][CH:22]([CH3:24])[CH3:23])[C:10]([C:25]([OH:27])=O)=[N:9]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]2[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[N:9]=[C:10]3[C:25](=[O:27])[N:21]([CH:22]([CH3:23])[CH3:24])[CH2:20][C:11]=23)=[CH:18][CH:17]=1
Reactant: CC(C)NCc1c(C(=O)O)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)N1Cc2c(nn(-c3ccccc3Cl)c2-c2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-4-(isopropylamino-methyl)-1H-pyrazole-3-carboxylic acid I-4d (40 mg, 0.074 mmol), EDC (28 mg, 0.148 mmol), HOAt (20 mg, 0.148 mmol), and triethylamine (0.02 ml, 0.148 mmol) in CH2Cl2 (10 ml) was stirred at room temperature for 17 hours. The reaction mixture was washed with sat'd aq NaHCO3, sat'd aq NaCl, dried and concentrated in vacuo. The crude residue was diluted with cyclohexane and stirred for 17 hours. A solid precipitated out of solution and was collected by filtration to give 3A-1 (11 mg, 38%): +APCI MS (M+1) 386.1; 1H NMR (CDCl3) δ 7.50-7.38 (m, 4H), 7.26 (d, 2H, J=9.6 Hz), 7.06 (d, 2H), 4.69 (m, 1H), 1.3 (d, 6H, J=6.65 Hz).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[Cl-].[Al+3].[Cl-].[Cl-].Cl.[CH:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClC1C=CC=CC=1Cl>[Cl:3][C:2]1[N:4]=[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:1]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirring mixture of 1 eq of cyanuric chloride and 3 eq of aluminum chloride in o-dichlorobenzene at ice bath temperature was added concentrated HCl (13 wt % based on cyanuric chloride). After 10 minutes, 1.95 eq of benzene was added and the reaction mixture stirred at ice bath temperature for 10 minutes. The cooling bath was removed, the reaction was allowed to warm to room temperature, and stirred. After 26 h at room temperature, an HPLC analysis indicated about 86% cyanuric chloride conversion to 2-chloro-2,6-bisphenyl-1,3,5-triazine. The stirring was continued for 24 h at room temperature. The HPLC analysis showed the cyanuric chloride conversion to 92% with >96% being 2-chloro-4,6-bisphenyl-1,3,5-triazine and less than 2% of 2,4,6-trisphenyl-1,3,5-triazine. The result was confirmed by LCMS.
Reaction SMILES: C[O:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([CH2:9][CH2:10]Br)=[O:8])=[CH:5][CH:4]=1.[ClH:14].[N:15]1([C:21]([C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[NH:29][C:28](=[O:33])[CH2:27][CH2:26]3)=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[C:34](=O)([O-])[O-:35].[K+].[K+].Cl>CN(C)C=O.O.CO>[OH2:2].[ClH:14].[CH3:34][O:35][C:5]1[CH:4]=[CH:3][CH:13]=[CH:12][C:6]=1[C:7]([CH2:9][CH2:10][N:18]1[CH2:19][CH2:20][N:15]([C:21]([C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[NH:29][C:28](=[O:33])[CH2:27][CH2:26]3)=[O:22])[CH2:16][CH2:17]1)=[O:8]
Reactant: COc1ccc(C(=O)CCBr)cc1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCc2cc(C(=O)N3CCNCC3)ccc2N1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: COc1ccccc1C(=O)CCN1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.7 Grams of 2-(4-methoxybenzoyl)ethyl bromide, 1.4 g of 6-(1-piperazinylcarbonyl)-3,4-dihydrocarbostyril monohydrochloride and 1.4 g of potassium carbonate were suspended in 40 ml of dimethylformamide, then the suspension thus prepared was stirred at room temperature for 2 hours. After the reaction was finished, the reaction mixture was poured in 150 ml of water, and extracted with ethyl acetate. The extract was washed with water, dried then the solvent was removed by evaporation. The residue thus obtained was dissolved in methanol, and the pH of the methanol solution was adjusted to about pH=1 with hydrochloric acid. The solvent was removed by evaporation, then the residue was recrystallized from ethanol-water to obtain 3 g of 6-{4-[(2-methoxybenzoyl)ethyl]-1-piperazinylcarbonyl}-3,4-dihydrocarbostyril monohydrochloride monohydrate. Melting point: 204°-205° C. (dec.). Colorless rhombohedral crystals.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[OH:28][C:29]1([CH2:33][C:34](O)=[O:35])[CH2:32][CH2:31][CH2:30]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34](=[O:35])[CH2:33][C:29]5([OH:28])[CH2:32][CH2:31][CH2:30]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)CC1(O)CCC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(CC1(O)CCC1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (62 mg, 56%), MS (ISP) m/z=443.5 [(M+H)+], mp 155° C., was prepared in accordance with the general method of example 5 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 2-(1-hydroxy-cyclobutyl)-acetic acid.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[CH3:13][O:14][N:15]=[CH:16][C:17]1[CH:22]=[C:21]([Cl:23])[C:20]([O:24][CH2:25][C@@H:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)=[C:19]([Cl:31])[CH:18]=1.C(N(CC)CC)C>ClCCl>[CH3:13][O:14][N:15]=[CH:16][C:17]1[CH:22]=[C:21]([Cl:23])[C:20]([O:24][CH2:25][C@@H:26]2[CH2:30][CH2:29][CH2:28][N:27]2[C:8]([C:7]2[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=2)=[O:9])=[C:19]([Cl:31])[CH:18]=1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: CON=Cc1cc(Cl)c(OC[C@@H]2CCCN2)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON=Cc1cc(Cl)c(OC[C@@H]2CCCN2C(=O)c2cn(C)nc2C(F)F)c(Cl)c1
Reaction time: 4 h
Yield: 57.3 %

Procedure:
At a temperature of 0° C., a solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.103 g; 0.53 mmol) in dichloromethane (4 ml) was added dropwise to a stirred solution of 3,5-dichloro-4-[(S)-1-pyrrolidin-2-ylmethoxy)-benzaldehyde O-methyl-oxime (0.16 g; 0.53 mmol), which was prepared in analogy as described for example P12, and triethylamine (146 μl; 1.05 mmol) in dichloromethane (7 ml). The ice bath was removed and reaction mixture was allowed stirring for 4 hours. The reaction mixture was washed with 2M HCl (10 ml), 1M NaOH (10 ml) and saturated NaCl (30 ml) and then dried over Na2SO4. After removal of the solvent, the residue (0.20 g in the form of an oil) was purified by flash chromatography over silica gel (eluent:cyclohexane/ethyl acetate 1:1). 0.14 g (57% of theory) of 3,5-dichloro-4-[(S)-1-(3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl)-pyrrolidin-2-ylmethoxy]-benzaldehyde O-methyl-oxime was obtained in form of an oil. 1H NMR (400 MHz, CDCl3): δ 1.95 (m, 1H), 2.20 (m, 2H), 2.45 (m, 1H), 3.68 (m, 2H), 3.96 (s, 3H, NCH3), 3.98 (s, 3H, OCH3), 4.22-4.24 (m, 1H), 4.38 (m, 1H), 4.61 (m, 1H), 7.01-7.28 (t, 1H, CHF2), 7.50 (s, 2H, Ar—H), 7.61 (s, 1H), 7.89 (s, 1H). MS [M+H]+ 361/363/365.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][CH:6]([CH2:11][P:12]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][CH:8]([CH3:10])[CH3:9])C.Cl>O1CCOCC1.O>[CH2:18]([O:17][P:12]([CH2:11][CH:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:5][C:4]([OH:20])=[O:3])([O:14][CH2:15][CH3:16])=[O:13])[CH3:19]
Reactant: CCOC(=O)CC(CC(C)C)CP(=O)(OCC)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCOP(=O)(CC(CC(=O)O)CC(C)C)OCC
Yield: 61.8 %

Procedure:
Lactam 6 (0.64 g, 3.87 mmol) was dissolved in 1,4-dioxane (4 mL) and hydrochloric acid (16 mL of a 6N solution), and the mixture was refluxed for 6 hours. After cooling, the mixture was diluted with water (20 mL) and washed with dichloromethane (2×15 mL). The aqueous layer was evaporated under reduced pressure to give acid 7 (0.67 g, 79%) as a white solid. Recrystallization using ethyl acetate/methanol gave Example 41 exclusively (0.26 g); δH (400 MHz; d6-DMSO) 7.98 (2H, br s, NH2), 3.13 (2H, s, CH2NH2), 2.70 (2H, s), 2.17–2.14 (4H, m), 1.85 (2H, dd, J 13.3, 8.0), 1.63 (2H, m), 1.55 (2H, dd, J 12.9, 5.1); m/z (ES+) 184 (M+H, 100%); LCMS (Prodigy C18, 50 mm×4.6 mmid column, 5–50% Acetonitrile/water) Retention Time=2.40 minutes, 98% purity.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:18][N:19]=[C:20]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[C:21]#[N:22])(=[O:17])=[O:16])=[CH:11][CH:10]=1.[C:28](Cl)(=[O:32])[C:29]([CH3:31])=[CH2:30]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:28]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:18][N:19]=[C:20]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[C:21]#[N:22])(=[O:17])=[O:16])=[CH:11][CH:10]=1)(=[O:32])[C:29]([CH3:31])=[CH2:30]
Reactant: C=C(C)C(=O)Cl
Reactant: N#CC(=NOS(=O)(=O)c1ccc(O)cc1)c1cccs1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)Oc1ccc(S(=O)(=O)ON=C(C#N)c2cccs2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 71.5 %

Procedure:
2.2 g (0.022 mole) of triethylamine and 0.5 g of 4-dimethylaminopyridine are added to a solution of 6.1 g (0.022 mole) of α-(4-hydroxybenzenesulfonyloxyimino)thien-2-ylacetonitrile (3a) in 75 ml of methylene chloride. With cooling to 0° C., a solution of 2.3 g (0.022 mole) of methacryloyl chloride in 20 ml of CH2Cl2 is added dropwise, and the reaction mixture is stirred for 3 hours at 0° C. The mixture is then filtered through silica gel, the filtrate is concentrated by evaporation, and the residue is recrystallised from methylene chloride/hexane, affording 5.92 g of the title compound with a melting point of 165°-166° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH2:13][C:14]([OH:16])=[O:15])C(O)=O)[CH:6]=[CH:7][CH:8]=1.[CH2:17](O)[CH3:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: CCO
Reactant: COc1cccc(C(CC(=O)O)C(=O)O)c1
Product: CCOC(=O)CCc1cccc(OC)c1
Yield: 93 %

Procedure:
A solution of 3-methoxyphenylsuccinic acid (1.500 g, 8.32 mmol) in dry ethanol (15 mL) with a small quantity of DOWEX™ strong acid ion exchange resin was refluxed for 22 h. The reaction mixture was filtered and the solvent evaporated in vacuo to give 1.618 g of ester 25. Yield 93%. 1H NMR (300 MHz, CDCl3) δ ppm: 7.15 (q, J=8.6 Hz, 1H), 6.72 (d, J=7.8 Hz, 1H), 6.65-6.70 (m, 2H), 4.06 (q, J=7.1 Hz, 2H), 3.72 (s, 3H), 2.86 (t, J=7.9 Hz, 2H), 2.54 (t, J=7.9 Hz, 2H), 1.17 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ ppm: 172.9, 159.7, 142.2, 129.4, 120.6, 114.0, 111.6, 60.4, 55.1, 35.8, 31.0, 14.2; HRMS (EI) m/z: calcd for C12H16O3: 208.1099. found: 208.1104.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].[CH3:24][C:25]1([CH3:38])[CH2:30][CH2:29][CH:28]([N:31]2[CH2:34][CH2:33][CH:32]2[C:35]([O-])=[O:36])[CH2:27][CH2:26]1.[Li+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:35]([CH:32]2[CH2:33][CH2:34][N:31]2[CH:28]2[CH2:29][CH2:30][C:25]([CH3:38])([CH3:24])[CH2:26][CH2:27]2)=[O:36])[C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: CC1(C)CCC(N2CCC2C(=O)[O-])CC1
Agent: [Li+]
Product: CC1(C)CCC(N2CCC2C(=O)N2C[C@H](S(=O)(=O)c3ccccc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)CC1

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H and lithium 1-(4,4-dimethylcyclohexyl)azetidine-2-carboxylate 20C carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(4,4-dimethylcyclohexyl)azetidine-2-carbonyl)pyrrolidine-2-carboxamide 1:1 epimers as an off-white solid (74%). MS ISP (m/e): 547.1 (100) [(M+H)]]+.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23]C(C)(C)C)=O)[CH2:17][CH2:16]1)=[O:7].C(O)(C(F)(F)F)=O.[NH:37]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@@H:38](C(O)=O)[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Cl:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][C@@H:38]([NH:37][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:21](=[O:23])[N:18]2[CH2:17][CH2:16][CH:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]3[CH:3]=[CH:4][NH:5][C:6]3=[O:7])[CH2:20][CH2:19]2)=[CH:45][CH:44]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: COC(CNC(=O)Nc1ccccc1C1CCN(C(=O)OC(C)(C)C)CC1)OC
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2-n2cc[nH]c2=O)CC1

Procedure:
The title compound was prepared according to the procedure described in Example 17 (Step b) using tert-butyl 4-(2-{[(2,2-dimethoxyethyl)amino]carbonylamino}phenyl)piperidine-carboxylate (Step a) (0.742 g, 1.82 mmol) and a 50% aqueous TFA soln (20 mL) followed by Boc-p-Cl-D-PheOH (Advanced ChemTech) (0.545 g, 1.82 mmol), EDC (Advanced ChemTech) (0.523 g, 2.73 mmol), HOBT (Novabiochem) (0.246 g, 1.82 mmol) and TFA (Aldrich) (0.25 mL, 1.82 mmol) in CH2Cl2 (10 mL). Purification by silica gel chromatography (100% EtOAc then 1:9 MeOH:EtOAc) provided the title compound as a white solid (0.675 g). MS (ESI, pos. ion) m/z: 525 (M+1). Calc'd for C28H33ClN4O4: 524.22.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N+:21]=2[O-])=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].C1CCCCC=1>[Pd].C(O)(C)C>[CH3:1][C:2]([CH3:27])([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(C)(C)Cc1ccc(OCCCNc2cccc[n+]2[O-])cc1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CC(C)O
Product: COC(=O)CC(C)(C)Cc1ccc(OCCCNc2ccccn2)cc1

Procedure:
A mixture of the product of STEP 1 (0.95 g), cyclohexene (Aldrich, 7 mL), 10% Pd/C (0.2 g) and isopropanol (10 mL) was heated to reflux for 20 hours. The mixture was filtered through celite and concentrated in vacuo. The residue was purified by chromatography using ethyl acetate as eluant to provide the above product as a thick gum.
Reaction SMILES: [C:1]([C@@H](C)C(N)(N)C(O)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[OH:23]C1C2N=NNC=2C=CC=1.Cl.C[N:35]([CH3:44])[CH2:36][CH2:37][CH2:38][N:39]=C=NCC>C1COCC1>[C:4]([O:3][C:1](=[O:2])[NH:39][C@H:38]1[CH2:37][CH2:36][NH:35][C:44]1=[O:23])([CH3:5])([CH3:6])[CH3:7]
Reactant: Oc1cccc2[nH]nnc12
Reactant: C[C@H](C(=O)OC(C)(C)C)C(N)(N)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 85.2 %

Procedure:
(S)-Boc-Diaminobutyric acid (25 g, 115 mmol), triethylamine (35 g, 344 mmol), and hydroxybenzotriazole (19.3 g, 143 mmol) are dissolved in THF (300 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (27.4 g, 143 mmol) is added to the solution. The solution is heated to 60° C. over 15 minutes. A white precipitate forms and the solution is kept at 60° C. for 4 hours. After this time, the solution is filtered and the collected liquid is concentrated. The crude product is purified by column chromatography in a gradient of 1% MeOH/CH2Cl2 to 3% MeOH/CH2Cl2 to afford the title compound (19.6 g, 98 mmol) as a white solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:11][C:10]2[CH:12]=[C:13]([Br:16])[CH:14]=[CH:15][C:9]=2[C:8]=1[CH3:17].[CH2:18]=[O:19].O>CCCCCC.CCOCC>[Br:16][C:13]1[CH:14]=[CH:15][C:9]2[C:8]([CH3:17])=[C:7]([CH2:18][OH:19])[S:11][C:10]=2[CH:12]=1
Reactant: Cc1c(Br)sc2cc(Br)ccc12
Reactant: C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: Cc1c(CO)sc2cc(Br)ccc12
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
A solution of n-butyl-lithium in hexane (13.2 ml of 1.55 M solution) was added dropwise to a stirred solution of 2.6-dibromo-3-methylbenzo[b]thiophene (6.60 g) in dry ether (150 ml) at 0° under dry nitrogen and the mixture was stirred at 0° for 30 minutes. Paraformaldehyde (0.71 g) was then added portionwise and the mixture was stirred at 0° for 3 hours. Water was added and the layers were separated. The ether layer was washed with water, dried (Na2SO4) and evaporated to give an oil which was chromatographed on silica gel. Elution with chloroform first gave some impurity followed by pure product. Evaporation of the product-containing fractions gave a solid which was crystallised from ethyl acetate/petrol (b.p. 60°-80°) to give 6-bromo-2-hydroxymethyl-3-methylbenzo[b]thiophene (3.20 g), m.p. 95°-96°.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([OH:14])([CH3:13])([CH3:12])[CH3:11]>C1(C)C=CC=CC=1>[C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9]
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1ccccc1
Temperature: 50 °C

Procedure:
Phenylisocyanate (500 g) and tert-butanol (500 mL) are mixed in toluene (500 mL) in a 2 L round bottom flask. The solution is stirred over night in a 50° C. water bath. The N-Boc aniline is collected by filtration to give the white solid (702 g).
Reaction SMILES: C1COCC1.[C:6]1([C@H:16]([N:18]([CH2:26][CH:27]2[CH:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:30][NH:29][CH2:28]2)C(=O)OC(C)(C)C)[CH3:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.Cl[C:39]([O:41][CH2:42][CH3:43])=[O:40].C(N(CC)CC)C>O>[C:6]1([C@H:16]([NH:18][CH2:26][CH:27]2[CH:31]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:30][N:29]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:28]2)[CH3:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCC1c1ccccc1)C(=O)OC(C)(C)C
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)N1CC(CN[C@H](C)c2cccc3ccccc23)C(c2ccccc2)C1
Temperature: 50 °C

Procedure:
A 10 ml THF solution of 500 mg of tert-butyl [(1R)-1-(1-naphthyl)ethyl][(4-phenylpyrrolidin-3-yl)methyl]carbamate was mixed with 0.34 ml of ethyl chloroformate and stirred at 50° C. A 0.24 ml portion of triethylamine and 20 ml of water were added thereto, and the solvent was evaporated. This was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate, and the solvent was evaporated. The thus obtained residue was treated with 4 M hydrogen chloride/ethyl acetate solution and recrystallized from ethyl acetate-hexane to obtain 312 mg of ethyl 3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidine-1-carboxylate as colorless crystals.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[I:5][C:6]1[C:7]([OH:16])=[C:8]([O:14][CH3:15])[CH:9]=[C:10]([CH:13]=1)[CH:11]=[O:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:16][C:7]1[C:6]([I:5])=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][C:8]=1[O:14][CH3:15])[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: COc1cc(C=O)cc(I)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1c(I)cc(C=O)cc1OC
Reaction time: 1 h

Procedure:
Allyl bromide (27.5 ml, 0.32 mol) was added to a solution of 5-iodovanillin (50.0 g, 0.18 mol) in DMF (200 ml) containing potassium carbonate (48 g, 0.35 mol) at 80° C. The mixture was stirred at this temperature for 1 hour, filtered, and the filtrate was evaporated to a residue, which was purified by HPLC (hexane-ethyl acetate, 4:1, v/v) to give 4-allyloxy-5-iodo-3-methoxybenzaldehyde.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([O:9][CH2:10][C@@H:11]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH:6]=[N:7][CH:8]=1)#[CH:2].Cl.Br[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1.CN(C=O)C.C(N(CC)CC)C>[Cu]I.C(OCC)(=O)C>[NH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]([CH2:12][C@H:11]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH2:10][O:9][C:5]2[CH:6]=[N:7][CH:8]=[C:3]([C:1]#[C:2][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)[CH:4]=2)=[CH:14]1
Reactant: Brc1ccncc1
Reactant: C#Cc1cncc(OC[C@H](Cc2c[nH]c3ccccc23)NC(=O)OC(C)(C)C)c1
Agent: [Cu]I
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](COc1cncc(C#Cc2ccncc2)c1)Cc1c[nH]c2ccccc12
Temperature: 50 °C
Reaction time: 20 h
Yield: 76.6 %

Procedure:
A mixture of Example 14B (150 mg, 0.384 mmol), 4-bromopyridine hydrochloride (75 mg, 0.34 mmol), Pd2Cl2(PPh3)2 (27 mg, 0.0384 mmol), and CuI (18 mg, 0.093 mmol), was purged with nitrogen, treated with DMF (4 mL) and triethylamine (214 μL, 1.54 mmol), stirred at 50° C. for 20 hours, cooled to room temperature, treated with ethyl acetate (50 mL), washed with brine, dried (MgSO4), filtered, and concentrated. The residual oil was purified by flash column chromatography on silica gel with 2:1 ethyl acetate/hexanes to provide the desired product (122 mg, 68%). MS (APCI) m/e 469 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].[C:9]1([CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCCCCC>[OH-].[Na+].O.C1C=CC=CC=1>[C:9]1([CH2:15][CH2:16][CH2:17][C:18]([N:1]2[CH2:8][CH2:7][CH2:6][C@@H:2]2[C:3]([OH:5])=[O:4])=[O:19])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)[C@H]1CCCN1
Reactant: O=C(Cl)CCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Solvent: c1ccccc1
Product: O=C(O)[C@H]1CCCN1C(=O)CCCc1ccccc1
Yield: 67.4 %

Procedure:
3.45 g of D-proline was dissolved in 60 ml of 1N of sodium hydroxide and 30 ml of water. To the solution thus obtained, a solution prepared by dissolving 5.56 g of 4-phenylbutanoyl chloride in 30 ml of benzene was added dropwise with stirring. Subsequently, 30 ml of 1N sodium hydroxide was further added and the mixture was stirred at room temperature overnight. The benzene layer was removed and the water layer was washed twice with 50 ml of ether. To this water layer was added 7% hydrochloric acid to acidify it, followed by extraction with 70 ml of ethyl acetate three times. The extract was dried over anhydrous sodium sulfate. Ethyl acetate was evaporated to obtain an oily residue, which was treated with hexane to obtain 5.28 g of N-(4-phenylbutanoyl)-D-proline as colorless crystals.