Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][NH2+:15][CH2:14][CH2:13]2)[O:9][N:8]=1.C(N(C(C)C)CC)(C)C.[C:27](OC(=O)C)(=[O:29])[CH3:28]>ClCCl>[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:27](=[O:29])[CH3:28])[CH2:14][CH2:13]2)[O:9][N:8]=1
Reactant: c1csc(-c2noc(C3CC[NH2+]CC3)n2)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC(c2nc(-c3cccs3)no2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
50 mg (1 eq.) of 4-(3-thiophen-2-yl[1,2,4]oxadiazol-5-yl)-piperidinium hydrochloride and 77 μl (3 eq.) of diisopropylethylamine were dissolved in 1 ml of dichloromethane. 39 μl (1.2 eq.) of acetic anhydride were added dropwise and the reaction medium was stirred for 2 hours at room temperature. The reaction medium was evaporated and the residue was taken up in 15 ml of ethyl acetate. The organic phase was washed with aqueous 1N sodium hydroxide solution (3×30 ml), with aqueous 1N hydrochloric acid solution (3×30 ml) and with saturated aqueous NaCl solution (30 ml), dried over MgSO4 and concentrated under reduced pressure to give 41 mg (98%) of the expected compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:30]=[CH:29][C:8](/[CH:9]=[CH:10]\[C:11]2[N:19]([CH3:20])[C:18]3[C:17](=[O:21])[N:16]([CH2:22][CH2:23][CH3:24])[C:15](=[O:25])[N:14]([CH2:26][CH2:27][CH3:28])[C:13]=3[N:12]=2)=[CH:7][CH:6]=1)=[O:4].O.[OH-].[Li+]>O1CCOCC1.O>[CH3:20][N:19]1[C:18]2[C:17](=[O:21])[N:16]([CH2:22][CH2:23][CH3:24])[C:15](=[O:25])[N:14]([CH2:26][CH2:27][CH3:28])[C:13]=2[N:12]=[C:11]1/[CH:10]=[CH:9]\[C:8]1[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:30][CH:29]=1
Reactant: CCCn1c(=O)c2c(nc(/C=C\c3ccc(C(=O)OC)cc3)n2C)n(CCC)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCn1c(=O)c2c(nc(/C=C\c3ccc(C(=O)O)cc3)n2C)n(CCC)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
Compound 8 (2.64 g, 6.44 mmol) obtained in Example 7 was dissolved in a solvent mixture of 60 ml of dioxane and 40 ml of water. To the solution was added 1.08 g (25.8 mmol) of lithium hydroxide monohydrate, and the resulting mixture was stirred at room temperature for one hour. After neutralization with 1N HCl, the mixture was extracted three times with ethyl acetate. The combined extract was dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The resulting crude crystals were recrystallized from toluene/cyclohexane to give 2.26 g (yield 89%) of Compound 18 as a yellow powder.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH3:23])[CH2:11][CH2:12][CH2:13][C:14]([CH3:22])=[CH:15][CH2:16][CH2:17][C:18](=[O:21])[CH2:19][Br:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH:10]([CH3:23])[CH2:11][CH2:12][CH2:13][C:14]1([CH3:22])[O:32][CH:15]1[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][Br:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=CCCC(=O)CBr)CCCC(C)COCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(CCCC1(C)OC1CCC(=O)CBr)COCc1ccccc1
Yield: 107.7 %

Procedure:
11-Benzyloxy-1-bromo-6,10-dimethyl-2-oxo-undec-5-ene (15.6 g, 41 mM) in methylene chloride (250 ml) is treated with 85% m-chloroperbenzoic acid (8.35 g, 41 mM) in methylene chloride (200 ml) at 0° C. for 3 hours. The reaction mixture is washed with brine, saturated sodium sulfite, brine and then dried (Na2SO4). The solvent is removed in vacuo to give crude 11-benzyloxy-1-bromo-6,10-dimethyl-5,6-epoxy-undecan-2-one (17.5 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=O)=[CH:2]1.[CH3:12][NH2:13].[BH4-].[Na+]>CO>[CH3:12][NH:13][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: CN
Reactant: O=Cc1c[nH]c2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of indole-3-carboxaldehyde (5.4 g, 34.1 mmole) in MeOH (30 mL) was added a solution of 2.0 M CH3NH2 in MeOH (51.3 mL, 102.6 mmole). The reaction was stirred at RT overnight, then was concentrated to a light yellow oil. This oil was dissolved in EtOH (40 nL), and NaBH4 (1.3 g, 34.1 mmole) was added. After 16 hrs the reaction was concentrated to a slurry and dissolved in 10% Na2CO3(100 mL). The aqueous solution was extracted with EtOAc (2×200 mL) and the combined organic fractions were dried over Na2SO4 and concentrated. Drying in high vacuum left the title compound (5.2 g, 94%) as a faintly yellow oil: MS (ES) m/e 161 (M+H)+.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH:11]([NH:15][C:16]([NH:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=1[CH:21]=[N:22][NH:23]3)=[O:17])[CH2:10][CH2:9]2)([CH3:5])[CH3:4])#[N:2]>CO>[C:1]([C:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C@H:11]([NH:15][C:16]([NH:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=1[CH:21]=[N:22][NH:23]3)=[O:17])[CH2:10][CH2:9]2)([CH3:5])[CH3:4])#[N:2]
Reactant: CC(C)(C#N)c1ccc2c(c1)CCC2NC(=O)Nc1cccc2[nH]ncc12
Solvent: CO
Product: CC(C)(C#N)c1ccc2c(c1)CC[C@H]2NC(=O)Nc1cccc2[nH]ncc12

Procedure:
The title compound was prepared by chiral separation of the corresponding racemic compound 1-[5-(cyano-isopropyl)-indan-1-yl]-3-(1H-indazol-4-yl)-urea (Ex. 57E) using a chiral column ChiralCel OD. [α]D: +35.4° (c: 1.04, MeOH). MS (ESI) m/z: 360.07 [M+H]+. 1H NMR (DMSO-d6) □: 1.69 (s, 6H), 1.87 (m, 1H), 2.47 (m, 1H), 2.89 (m, 1H), 2.98 (m, 1H), 5.19 (q, 1H), 6.73 (d, 1H), 7.08 (d, 1H), 7.22 (t, 1H), 7.39 (s, 2H), 7.44 (s, 1H), 7.66 (d, 1H), 8.04 (s, 1H), 8.59 (s, 1H), 13.00 (s, 1H). Anal Calcd for C21H21N5O.0.3H2O: C, 69.14; H, 5.97; N, 19.20. Found: C, 69.08; H, 5.95; N, 19.31.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[N:13]([CH2:14][CH3:15])[N:12]=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:10]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])=[O:34])=[CH:29][CH:28]=1>>[CH:1]1([CH:7]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:34])=[CH:31][CH:32]=2)[C:9]2[N:13]([CH2:14][CH3:15])[N:12]=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: CCn1nc(-c2ccc(C(F)(F)F)cc2)cc1C(O)C1CCCCC1
Product: CCn1nc(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 19.5 %

Procedure:
Using cyclohexyl{1-ethyl-3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}methanol (0.6 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.42 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.18 g, 20%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:9][C:10]1[C:11](=[O:22])[O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[C:14]=2[C:15]=1[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:23]([O:26][CH2:27][CH2:28][CH2:29]Br)(=[O:25])[CH3:24]>>[CH2:1]([O:9][C:10]1[C:11](=[O:22])[O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:29][CH2:28][CH2:27][O:26][C:23](=[O:25])[CH3:24])[C:14]=2[C:15]=1[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1c(O)c2c(O)cccc2oc1=O
Reactant: CC(=O)OCCCBr
Product: CCCCCCCCOc1c(O)c2c(OCCCOC(C)=O)cccc2oc1=O

Procedure:
In the same manner as in Reference Example 1, except that an equimolar amount of 3-octyloxy-4,5-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-ethoxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and 3-bromopropyl acetate was used in place of 2-bromoethyl acetate in Reference Example 1, 3-octyloxy-4-hydroxy-5-(3-acetoxypropoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH:6]=[C:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.Br[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[C:15]([NH:14][C:10]1[CH:9]=[C:8]([C:5]2[CH2:6][CH2:7][N:2]([CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:3][CH:4]=2)[CH:13]=[CH:12][CH:11]=1)(=[O:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: CC(=O)Nc1cccc(C2=CCNCC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(C2=CCN(CCCNC(=O)OC(C)(C)C)CC2)c1

Procedure:
A solution of N1-[3-(1,2,3,6-tetrahydro-4-pyridinyl) phenyl]acetamide hydrochloride (8.24 mmol), tert-butyl N-(3-bromopropyl)carbamate and potassium carbonate (33 mmol) in dry dioxane (30 mL) was heated at reflux temperature overnight. The solids were removed by filtration, the solution was concentrated in vacuo and the product was chromatographed, giving the desired product (110 mg). 1H NMR δ 7.65 (s, 1 H), 6.98 (s, 1 H), 7.45 (d, 1 H, J=7.8 Hz), 7.16 (apparent t, 1 H, J=7.8 Hz), 7.10 (d, 1 H, J=7.8 Hz), 6.02 (s, 1 H), 5.23 (b, 1 H), 3.40 (b, 2 H), 3.30-1.80 (m, 10 H), 2.18 (s, 3 H), 1.45 (s, 9 H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][NH:17][C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Cl[CH2:24][C:25]#[N:26].[H-].[Na+]>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][N:17]([CH2:24][C:25]#[N:26])[C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:21][CH:22]=1
Reactant: COc1ccc(C(=O)C2CCN(C3CCNC3=O)CC2)cc1
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)C2CCN(C3CCN(CC#N)C3=O)CC2)cc1
Temperature: 70 °C

Procedure:
To a solution of 3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-pyrrolidin-2-one (1.65 mmol, 500 mg) and chloroacetonitrile (1.65 mmol, 0.125 g) in THF (30 mL) and DMF (5 mL) was added sodium hydride (60%, 2.48 mmol, 0.099 g) and heated to 70° C. for 30 min. The reaction was allowed to cool to ambient temperature and dried under vacuum. Flash column chromatography (silica) was performed eluting with ethyl acetate to 20% MeOH/ethyl acetate and provided the title compound as an off-white residue (125 mg, 22.1% yield). Calculated MS=341.4. found MS (ESI) m/e 342.9 (M+H+); HPLC (Novapak 150×3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time=2.472 min.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH2:8].Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[N:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>CN1CCCC1=O>[Cl:20][C:16]1[CH:15]=[C:14]2[C:19]([C:10]([NH:1][C@H:2]3[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]3[NH2:8])=[CH:11][CH:12]=[N:13]2)=[CH:18][CH:17]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: N[C@H]1CCCC[C@@H]1N
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: N[C@H]1CCCC[C@@H]1Nc1ccnc2cc(Cl)ccc12

Procedure:
13.6 g of (1S,2S)-(+)-1,2-diaminocyclohexane, 23.6 g of 4,7-dichloroquinoline and 16.6 ml of triethylamine were held at 150° C. in 150 ml of 1-methyl-2-pyrrolidone under argon for 16 hrs. The solvent was largely distilled off at 0.1 Torr/80° C. and the residue was triturated with 300 ml of 1.5N HCl. The resulting aqueous suspension was extracted three times with 300 ml of dichloromethane and then made basic with concentrated ammonia, with gum-like clumps separating. The supernatant solution was decanted off and extracted twice with 400 ml of dichloromethane. The crude product obtained from these extracts was purified by two-fold flash chromatography on neutral aluminium oxide (Brockmann activity II) with dichloromethane and dichloromethane/ethanol 30:1. Crystallization was effected from 40 ml of dichloromethane and 60 ml of ethyl acetate by distillation of the former. Yield: 4 g (12%) of (1S,2S)-N-(7-chloro-quinolin-4-yl)-cyclohexane-1,2-diamine; m.p. 160° C., [α]D =+129.30 (MeOH, c=1.0).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10]([CH2:21][O:22][CH2:23][C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=2)[CH2:9]1)=O)(C)(C)C.[ClH:38].CO>>[ClH:38].[F:33][C:30]([F:31])([F:32])[C:28]1[CH:29]=[C:24]([CH:25]=[C:26]([C:34]([F:35])([F:36])[F:37])[CH:27]=1)[CH2:23][O:22][CH2:21][C@H:10]1[C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(F)cc2)[C@H](COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Agent: Cl
Solvent: CO
Product: Fc1ccc([C@@H]2CCNC[C@H]2COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1

Procedure:
A solution of (−)-(3S,4R)-3-(3,5-bis-trifluoromethyl-benzyloxymethyl)-4-(4-fluoro-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (1.10 g, 2.05 mmol) in a 1.25 M solution of hydrochloric acid in methanol (16.4 ml, 3.3 mmol) was stirred for 30 min. at 40° C. The reaction mixture was concentrated to dryness and the residue was partitioned between tert-butyl methyl ether and a 1 M aqueous sodium hydroxide solution. After extraction with three portions of tert-butyl methyl ether the combined organic layers were dried over sodium sulfate and concentrated in vacuo to 0.890 g (99.5%) of the title compound as a colorless white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[C:17](=[O:19])[N:16]([CH3:20])[CH2:15][CH2:14]3)[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[C:24]([CH3:31])=[N:25][N:26]([CH2:28][CH2:29][OH:30])[CH:27]=1.CCOC(C)=O>CO>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[C:17](=[O:19])[N:16]([CH3:20])[CH2:15][CH2:14]3)=[CH:7][C:2]([NH:22][C:23]2[C:24]([CH3:31])=[N:25][N:26]([CH2:28][CH2:29][OH:30])[CH:27]=2)=[N:3][CH:4]=1
Reactant: Cc1nn(CCO)cc1N
Reactant: CN1CCc2cccc(Nc3cc(Cl)ncc3Cl)c2C1=O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nn(CCO)cc1Nc1cc(Nc2cccc3c2C(=O)N(C)CC3)c(Cl)cn1

Procedure:
This compound was prepared from 8-[(2,5-dichloropyridin-4-yl)amino]-2-methyl-3,4-dihydroisoquinolin-1-one and 2-(4-amino-3-methyl-pyrazol-1-yl)ethanol. Column chromatography (SiO2, 50 equiv.; 95:5; EtOAc:MeOH) followed by prep. TLC (SiO2: 20×20 cm; 1000 μM, Analtech, EtOAc:MeOH; 95:5) furnished 45 mg of the desired compound. 1H NMR spectrum (CDCl3) 2.09 (s, 3H), 2.91 (t, 2H), 3.11 (s, 3H), 3.25 (bs, 1H), 3.51 (t, 2H), 3.86-3.95 (m, 2H), 4.05-4.10 (m, 2H), 5.89 (s, 1H), 6.44 (s, 1H), 6.68 (d, 1H), 7.14-7.29 (m, 2H), 7.44 (s, 1H), 7.88 (s, 1H), 11.09 (s, 1H); Mass spectrum: ESI+ MH+ 427
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:14][CH:15]([C:20]23OCC(C)(C[O:25]2)C[O:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])[C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.Cl>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:14][C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:20]([OH:25])=[O:21])[C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: CC(C)CC(NC(c1ccc(Br)cc1)c1nccs1)C12OCC(C)(CO1)CO2
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@H](N[C@@H](c1ccc(Br)cc1)c1nccs1)C(=O)O
Reaction time: 2 h

Procedure:
To a solution of [(4-bromo-phenyl)-thiazol-2-yl-methyl]-[3-methyl-1-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-butyl]-amine (500 mg, 1.06 mmol) in THF (20 mL) and water (18 mL), was added 1N HCl (3.5 mL). The reaction mixture was stirred for 2 h. After checking the TLC for the disappearance of the starting material, Li(OH).H2O (280.2 mg, 6.3 eq.) was added and stirred at room temperature for 2 h. Then 1N HCl was added to adjust the pH 4-6, and the product was extracted with BOAC and the organic layer dried over MgSO4. The solvent was evaporated to yield (2S)-2-{(S)-[(4-bromophenyl)-thiazol-2-yl-methyl]-amino}-4-methylpentanoic acid as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:4]([CH2:16]Br)[N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:6]=1[Br:7].[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])(=[O:32])=[O:31])=[CH:26][CH:25]=1.[H-].[Na+]>C1COCC1>[Br:1][C:2]1[C:3]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:4]([CH2:16][N:33]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[S:30]([C:27]2[CH:26]=[CH:25][C:24]([CH3:23])=[CH:29][CH:28]=2)(=[O:32])=[O:31])[N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:6]=1[Br:7]
Reactant: CCOC(=O)c1c(Br)c(Br)n(Cc2ccc(F)cc2)c1CBr
Reactant: CCOC(=O)CNS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN(Cc1c(C(=O)OCC)c(Br)c(Br)n1Cc1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution of ethyl 4,5-dibromo-2-(bromomethyl)-1-(4-fluorobenzyl)-1H-pyrrole-3-carboxylate (104.0 g, 0.209 mol) and ethyl N-[(4-methylphenyl)sulfonyl]glycinate (53.7 g, 0.209 mol, prepared by the method of: Ginzel, K. D.; Brungs, P.; Steckhan, E. Tetrahedron 1989, 45, 1691-1701) in anhydrous THF (1.5 L) was added NaH (60% in mineral oil, 8.40 g, 0.210 mol) in several small portions. The mixture was allowed to stir at room temperature for 16 hours. It was quenched with aq. NH4Cl solution, and extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated and the residue was purified by column chromatography with ethyl acetate/hexane (1:4, v:v) to provide the title compound as glue-like material (124 g, 88% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[C:9]([CH3:20])=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:30]2[CH:35]=[CH:34][C:33]([C:36]3([C:39]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])=[O:40])[CH2:38][CH2:37]3)=[CH:32][CH:31]=2)O1>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[C:9]([CH3:20])=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:30]2[CH:31]=[CH:32][C:33]([C:36]3([C:39]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])=[O:40])[CH2:38][CH2:37]3)=[CH:34][CH:35]=2)=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)(C)C
Reactant: CC1(C)OB(c2ccc(C3(C(=O)NS(C)(=O)=O)CC3)cc2)OC1(C)C
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1NC(=O)OC(C)(C)C

Procedure:
Prepared according to the procedure described in Example 166, Step 3, using [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid tert-butyl ester and N-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarbonyl}-methanesulfonamide.
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:12](N(CC)CC)C.CI>C(Cl)Cl>[CH3:12][S:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CCN(CC)CC
Reactant: Oc1ccc2nc(S)oc2c1
Solvent: CI
Solvent: ClCCl
Product: CSc1nc2ccc(O)cc2o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the 2-mercaptobenzo[d]oxazol-6-ol (1.55 g, 9.28 mmol, 1.0 eq) in 20 mL of methylene chloride was added triethylamine (1.87 g, 18.56 mmol, 2.0 eq) and methyl iodide (1.77 g, 13.92 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred at rt for 3 hours. The mixture was diluted with 100 mL of methylene chloride. The resulting mixture was washed with water (10 mL), brine (10 mL), then dried over MgSO4, filtered, and evaporated under reduced pressure to give crude product, which was purified by silica gel column eluted with ethyl acetate and hexane to give the titled compound. MH+=182.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:13]([C:16]1[N:21]=[CH:20][C:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)[CH2:14][CH3:15]>CN(C=O)C.O>[N:1]1([CH:13]([C:16]2[N:21]=[CH:20][C:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[CH2:14][CH3:15])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCC(Br)c1ccc(-c2ccc(C(N)=O)cc2)cn1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(c1ccc(-c2ccc(C(N)=O)cc2)cn1)n1ccnc1
Temperature: 57.5 °C
Yield: 13 %

Procedure:
To a solution of imidazole (0.077 g, 1.12 mmol), in DMF (15 mL) was added potassium carbonate (0.26 g, 1.87 mmol) and 4-(6-(1-bromopropyl)pyridin-3-yl)benzamide under nitrogen and the solution was heated to 55-60° C. for 6 h. The contents were cooled to rt, diluted with water (100 mL), extracted with ethyl acetate (2×100 mL), the layers separated, the organic layer washed with brine solution (2×30 mL), the organic layer dried over sodium sulphate and distilled off to get the crude product. The product was purified by preparative TLC (2000; 5% methanol in ethyl acetate) to give 4-(6-(1-(1H-imidazol-1-yl)propyl)pyridin-3-yl)benzamide (15 mg, 13% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.92 (s, 1H), 8.13 (d, 1H), 8.11 (s, 1H), 7.97 (d, 2H), 7.80 (t, 3H), 7.40 (d, 2H), 7.31 (s, 1H), 6.89 (s, 1H), 5.38 (q, 1H), 2.27 (m, 2H), 0.82 (t, 3H); LC-MS m/z calcd for [M+H]+ 307.37. found 307.3.
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]([NH2:13])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([CH3:12])=[CH:8]2.[N-:14]([C:17]#[N:18])[C:15]#[N:16].[Na+]>CN(C)C=O>[C:15]([N:14]=[C:17]([NH2:18])[NH:13][C:5]1[CH:6]=[C:7]2[C:11](=[C:3]([I:2])[CH:4]=1)[NH:10][C:9]([CH3:12])=[CH:8]2)#[N:16]
Reactant: N#C[N-]C#N
Reactant: Cc1cc2cc(N)cc(I)c2[nH]1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2cc(NC(N)=NC#N)cc(I)c2[nH]1
Temperature: 45 °C
Reaction time: 2.5 h
Yield: 42.1 %

Procedure:
A solution of 7-iodo-2-methyl-1H-indol-5-ylamine hydrochloride XVII (1.9 g, 6.158 mmol) in N,N-dimethylformamide (30 mL) at 25° C. was treated with sodium dicyanamide (1.37 g, 15.397 mmol) and then warmed to 45° C. for 4 h. The resulting mixture filtered and concentrated in vacuo and the residue treated with water (20 mL). The resulting mixture was allowed to stand at 25° C. for 2.5 h during which time a solid formed. The solid was collected by filtration and washed with water, resuspended in methanol, filtered and dried to give N″-cyano-N-(7-iodo-2-methyl-1H-indol-5-yl)guanidine XVIII (0.88 g, 42%) as a light grey solid: LRMS for C11H10IN5 (M−H)+ at m/z=338.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH:10]([CH3:14])[C:11]([OH:13])=O)=[O:8])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24])[NH2:19].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:11]([CH:10]([NH:9][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:8])[CH3:14])=[O:13])[CH:20]=[CH:21][C:22]=1[C:23]([N:25]1[CH2:26][CH2:27][CH2:28][CH2:29]1)=[O:24]
Reactant: Nc1ccc(C(=O)N2CCCC2)c(Cl)c1
Reactant: CC(NC(=O)c1ccc(Cl)s1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(NC(=O)c1ccc(Cl)s1)C(=O)Nc1ccc(C(=O)N2CCCC2)c(Cl)c1

Procedure:
Prepared analogously to Example 1a from 2-[(5-chloro-thiophene-2-carbonyl)-amino]-propionic acid and 3-chloro-4-(pyrrolidin-1-yl-carbonyl)-aniline with TBTU and NMM in DMF.