Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[S:6][N:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[CH:3]=1.[Na+].[CH2:17]([N:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:25](=[S:27])[S-:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[I-].[Na+]>C(O)C>[CH2:28]([N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:25]([S:27][C:2]1[S:6][N:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[CH:3]=1)=[S:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=c1cc(Cl)sn1CCc1ccccc1
Reactant: S=C([S-])N(Cc1ccccc1)Cc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: O=c1cc(SC(=S)N(Cc2ccccc2)Cc2ccccc2)sn1CCc1ccccc1

Procedure:
To a solution of 4.8 g. (0.02 mole) of 5-chloro-2-phenethyl-4-isothiazolin-3-one in 35 ml of ethanol was added 5.9 g. (0.02 mole) of N,N-dibenzyldithiocarbamic acid sodium salt followed by 0.15 g. sodium iodide. The mixture was concentrated in vacuo and the residue was treated with 300 ml of boiling hexane under reflux. The hexane solution decanted and cooled to give 0.63 g. of the named product, mp 98°-100°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:18])[N:8]([CH3:17])[C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:5])[CH3:2].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:18])[N:8]([CH3:17])[C:9]2[C:14]([C:15]=1[N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: C1CCNC1
Reactant: CCOC(=O)c1c(Cl)c2cccnc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(N2CCCC2)c2cccnc2n(C)c1=O

Procedure:
A stirred mixture of 2.7 g. (0.01 mole) of 4-chloro-1,2-dihydro-1-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 0.7 g. (0.01 mole) of pyrrolidine and 1.06 g. (0.01 mole) of sodium carbonate in 25 ml. of ethanol was heated under reflux for 5 hours. The mixture was filtered and the filtrate was cooled in ice. The precipitate which formed was collected and was dissolved in 20 ml. of ethyl acetate. The solution was diluted with petroleum ether to the cloudy point. The precipitate which formed was collected to yield 0.5 g. of product, m.p. 118°-120° C.
Reaction SMILES: Br[CH:2]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:3]([C:5]1[CH:16]=[CH:15][C:8]2[N:9]=[N:10][N:11]([CH:12]([CH3:14])[CH3:13])[C:7]=2[CH:6]=1)=O.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[C:31]([C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)(=[NH:33])[NH2:32].O>CN(C)C=O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:2]2[N:33]=[C:31]([C:34]3[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=3)[NH:32][C:3]=2[C:5]2[CH:16]=[CH:15][C:8]3[N:9]=[N:10][N:11]([CH:12]([CH3:14])[CH3:13])[C:7]=3[CH:6]=2)=[CH:18][CH:19]=1
Reactant: CC(C)n1nnc2ccc(C(=O)C(Br)c3ccc(F)cc3)cc21
Reactant: N=C(N)c1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1nnc2ccc(-c3[nH]c(-c4cccnc4)nc3-c3ccc(F)cc3)cc21
Temperature: 50 °C
Yield: 39.1 %

Procedure:
To a stirred solution of 29 mg of 2-bromo-2-(4-fluoro-phenyl)-1-(3-isopropyl-3H-benzotriazol-5-yl)-ethanone in 0.38 mL of N,N-dimethylformamide was added 75 mg of cesium carbonate and 24 mg of 3-amidinopyridine hydrochloride. The mixture was heated at 50° C. for 30 min. The orange-brown mixture was cooled to 22° C., transferred to a separatory funnel with water, and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried (sodium sulfate), filtered, and the filtrate was concentrated to an orange oil. This oil was purified by flash chromatography (eluting with ethyl acetate) to give 12 mg of 6-[5-(4-fluoro-phenyl)-2-pyridin-3-yl-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole as a white solid. LCMS m/z 399 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([S:11]([NH2:14])(=[O:13])=[O:12])[C:5]=2[N:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:21]([N:25]=[C:26]=[O:27])[CH2:22][CH2:23][CH3:24].Cl>CC(=O)CC>[CH2:21]([NH:25][C:26]([NH:14][S:11]([C:10]1[C:5]2[N:4]=[N:3][N:2]([CH3:1])[C:6]=2[CH:7]=[CH:8][CH:9]=1)(=[O:13])=[O:12])=[O:27])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN=C=O
Reactant: Cn1nnc2c(S(N)(=O)=O)cccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1cccc2c1nnn2C
Temperature: 0 °C

Procedure:
To a stirred mixture of 1-methyl-1H-benzotriazole-4-sulfonamide (7.5 g), potassium carbonate (5.1 g), and 2-butanone (250 mL) was added butylisocyanate (3.9 mL) under an inert atmosphere. The reaction was heated at reflux for 15 hours. The cooled reaction mixture was poured into ice (500 mL), acidified with concentrated hydrochloric acid, and extracted with ethyl acetate-tetrahydrofuran. The extracts were dried over magnesium sulfate, filtered, and evaporated. The crude solid was washed with chlorobutane-hexanes and air dried to give 8.65 g of the title compound as a white solid, m.p. 170°-173° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])=[N:6][CH:7]=1.[H-].[Na+].Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([F:31])=[CH:27][C:28]=2[F:30])[N:23]=[C:22]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[C:21]=1[CH3:38].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:16][C:20]2[C:29]3[C:24](=[CH:25][C:26]([F:31])=[CH:27][C:28]=3[F:30])[N:23]=[C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[C:21]=2[CH3:38])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])=[N:6][CH:7]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Reactant: COc1ccccc1-c1ncc(Br)cc1N
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1-c1ncc(Br)cc1Nc1c(C)c(-c2ccccn2)nc2cc(F)cc(F)c12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A dry flask containing 5-bromo-2-(2-methoxyphenyl)pyridin-3-amine (194.5 mg, 0.7 mmol) in dry DMF (5 mL) was cooled to 0° C., then sodium hydride, 60% dispersion in mineral oil (90.8 mg, 2.27 mmol) was added carefully in portions. The mixture was stirred at 0° C. for 15 min, then 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (308.7 mg, 1.06 mmol) was added in portions. Upon complete addition, the mixture was warmed to 70° C. After 3 h, the reaction was cooled to rt then was carefully treated with 10% sodium carbonate solution. The black mixture was subsequently extracted 5 times with DCM:MeOH (90:10). The organic extraction was then washed one time with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on basic alumina (0-35% EtOAc in hexanes) to afford a yellow residue as mostly N-(5-bromo-2-(2-methoxyphenyl)pyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine that was used without further purification.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:34])[N:6]([CH3:33])[C:7]2[C:12]([C:13]=1[NH:14][C:15](=O)[CH3:16])=[CH:11][C:10]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[C:9]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[Cl:32])[N:8]=2)(=[O:3])[CH3:2].[CH3:35][Mg+].[Br-]>C1COCC1>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:10]2[C:9]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[Cl:32])=[N:8][C:7]3[N:6]([CH3:33])[C:5](=[O:34])[C:4]4[C:1]([CH3:2])([CH3:35])[O:3][C:15]([CH3:16])=[N:14][C:13]=4[C:12]=3[CH:11]=2)=[CH:23][CH:22]=1
Reactant: CC(=O)Nc1c(C(C)=O)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC1=Nc2c(c(=O)n(C)c3nc(-c4ccc(Cl)cc4Cl)c(-c4ccc(Cl)cc4)cc23)C(C)(C)O1

Procedure:
To the product of Example 1 (59.5 mg) in THF (2 mL) at 0° C. was added 0.52 mL MeMgBr solution (1.4 M, 75% toluene/25% THF). After 10 min the reaction was quenched with saturated aqueous NH4Cl and then diluted with EtOAc. The solution was washed with 10% aqueous NaHSO4 followed by aqueous NaHCO3/NaOH (4:1) before drying (Na2SO4). The concentrated residue was purified by preparative TLC (silica gel) eluted with 15% EtOAc in hexane affording the title compound. HPLC/MS: 512.0 (M+1), 514.0 (M+3); Rt=5.14 min.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH:12]=2)=[CH:5][N:4]=[CH:3]1.[BH4-].[Na+].[Cl-].[NH4+]>CO>[CH3:1][N:2]1[C:6]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]2[OH:13])=[CH:5][N:4]=[CH:3]1
Reactant: Cn1cncc1C1=CCCCC1=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Cn1cncc1C1CCCCC1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
To a solution of the 2-(1-methyl-1H-imidazol-5-yl)cyclohex-2-en-1-one (80 mg, 0.454 mmol) prepared in Example 49a in methanol (2.0 mL), sodium borohydride (50 mg, 1.32 mmol) was added at room temperature, and the reaction solution was stirred at room temperature for 30 minutes. To the reaction solution, a saturated aqueous solution of ammonium chloride (20 mL) was added, followed by extraction with dichloromethane (50 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate and vacuum concentrated to yield the title compound (50 mg, 61%) in the form of a trans/cis (2:1) mixture as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.Br[CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:15][CH2:14][CH2:13][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1
Reactant: ClCCBr
Reactant: CCOC(=O)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1CCCN(CCCl)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of ethyl 3-piperidylcarboxylate (100 g, 0.64 mole) in acetone (600 ml) was treated with 1-bromo-2-chloroethane (54 ml, 0.64 mole) and anhydrous potassium carbonate (138 g, 1.00 mole) and the mixture stirred at room temperature for 24 h. The mixture was concentrated in vacuo and the residue treated with water (400 ml) and extracted with ether (2×200 ml). The combined ether extracts were dried (Na2SO4) and concentrated in vacuo to leaye a yellow oil, which was purified by chromatography on silica gel eluting with 50% ether/60-80 petrol to give the title compound (D18) as a pale yellow oil (50.0 g, 36%). 1H Nmr (CDCl3) δ
Reaction SMILES: [Na].[OH:2][N:3]1[C:7](=[O:8])[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=[O:13].[CH3:14][N:15]=[C:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[O:8]=[C:7]1[C:6]2[C:5](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4](=[O:13])[N:3]1[O:2][C:16](=[N:15][CH3:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN=C(Cl)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CN=C(ON1C(=O)c2ccccc2C1=O)c1ccccc1

Procedure:
N-hydroxy phthalimide sodium salt (46.25 g.; 0.25 mol), is dissolved in dry DMF (220 ml), to the resulting suspension 38.8 g (0.25 mol) of N-methyl benzimidoyl chloride (prepared according to J. C. S. Perkin II, 1324, (1980)) are slowly added at room temperature, on stirring. The reaction mixture is stirred at room temperature for 19 h and then poured into 1.5 l of water. The so formed precipitate is sucked off and dried in vacuo to obtain 66.06 g of a a crude product which is then taken up in 250 ml of acetonitrile. After filtration 58.7 g of N-methyl-benzimidic acid 1,3-dioxo-1,3-dihydro-isoindol-2-yl ester are obtained in form of colorless crystals, mp. 174-176° C.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([N:11]=[C:12](SC)SC)=[N:10][C:5]2=[CH:4][CH:3]=1.Cl.Cl.[NH2:19][CH2:20][C@@:21]1([OH:28])[C@H:26]2[CH2:27][N:23]([CH2:24][CH2:25]2)[CH2:22]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O.C(Cl)(Cl)Cl>[F:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12]3[O:28][C@@:21]4([C@H:26]5[CH2:27][N:23]([CH2:24][CH2:25]5)[CH2:22]4)[CH2:20][N:19]=3)=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: CSC(=Nc1nc2ccc(F)nc2s1)SC
Reactant: NC[C@]1(O)CN2CC[C@@H]1C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Fc1ccc2nc(NC3=NC[C@@]4(CN5CC[C@@H]4C5)O3)sc2n1
Temperature: 100 °C

Procedure:
To a solution of dimethyl 5-fluorothiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate (95 mg, 0.349 mmol) in N,N-dimethylformamide (2 mL) was added (3S*,4R*)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol dihydrochloride (75 mg, 0.349 mmol). The reaction was then treated with cesium carbonate (114 mg, 0.7 mmol). The reaction was heated to 100° C. for 1 hour and then cooled to room temperature. The reaction was diluted with water (20 mL) and chloroform (2×20 mL). The organic phases were combined and concentrated to residue in vacuo. The residue was then triturated in diethyl ether to give (3R*,4R*)—N-(5-fluorothiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine as a precipitate (42 mg, 37%) that was collected via vacuum filtration. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.13 (br. s., 1H) 8.07 (dd, J=8.53, 7.28 Hz, 1H) 7.16 (dd, J=8.53, 1.51 Hz, 1H) 3.85 (d, J=10.29 Hz, 1H) 3.66 (d, J=10.29 Hz, 1H) 2.77-2.98 (m, 2H) 2.71 (td, J=6.65, 4.02 Hz, 2H) 2.58-2.67 (m, 2H) 2.40 (dd, J=10.16, 3.64 Hz, 1H) 1.87-2.00 (m, 1H) 1.53 (t, J=4.39 Hz, 1H). MS (LC/MS) R.T.=0.675 min; (M+H=320.1).
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[NH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[OH:30]>>[CH3:13][C:12]1[C:7]([NH:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]2[OH:30])=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: NC1CCCCC1O
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2O)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using 2-aminocyclohexanol instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (400 MHz, methanol-d6) δ ppm 1.16-1.22 (m, 1H), 1.30-1.41 (m, 3H), 1.50-162 (m, 3H), 1.68-1.74 (m, 1H), 1.91 (s, 3H), 2.20 (s, 3H), 3.72 (bs, 1H), 3.79 (bs, 1H), 4.61 (bs, 2H), 7.18-7.26 (m, 1H), 7.34-7.45 (m, 1H), 7.70-7.82 (m, 1H), 8.47 (bs, 1H); MS (ESI) m/z 328.8 (M+1)+.
Reaction SMILES: C1([Li])C=CC=CC=1.[Cl-].[C:9]1([CH2:14][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:13][CH:12]=[CH:11][CH:10]=1.[CH2:34]([N:38]([CH2:51][CH2:52][CH2:53][CH3:54])[C:39]1[CH:44]=[CH:43][C:42]([CH:45]=[CH:46][CH:47]=O)=[C:41]([O:49][CH3:50])[CH:40]=1)[CH2:35][CH2:36][CH3:37].O>O1CCCC1.C(OCC)(=O)C>[CH2:34]([N:38]([CH2:51][CH2:52][CH2:53][CH3:54])[C:39]1[CH:44]=[CH:43][C:42]([CH:45]=[CH:46][CH:47]=[CH:14][C:9]2[S:13][CH:12]=[CH:11][CH:10]=2)=[C:41]([O:49][CH3:50])[CH:40]=1)[CH2:35][CH2:36][CH3:37]
Reactant: c1ccc([P+](Cc2cccs2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCN(CCCC)c1ccc(C=CC=O)c(OC)c1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCN(CCCC)c1ccc(C=CC=Cc2cccs2)c(OC)c1
Reaction time: 2 h
Yield: 72 %

Procedure:
In a stream of argon, to 15 ml of tetrahydrofuran was added 1.68 g of phenyllithium (19% solution in dibutylether) (3.8 mmol), and 1.37 g (3.5 mmol) of 2-thenyl triphenylphosphonium chloride was added thereto under ice cooling. Next, 1.0 g (3.5 mmol) of 3-(4-dibutylamino-2-methoxyphenyl)propenal was dissolved in tetrahydrofuran and added dropwise. The mixture was stirred under ice cooling for 2 hours. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography to give 0.92 g of an orange oily matter (yield: 72.0%).
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[NH:7][CH2:8][C:9]([OH:11])=[O:10].[CH3:12]O>>[ClH:1].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[NH:7][CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: CO
Reactant: O=C(O)CNc1cccs1
Agent: Cl
Product: COC(=O)CNc1cccs1
Temperature: 50 °C

Procedure:
Gaseous HCl is passed into a solution of 6.8 g of 2-thienylaminoacetic acid in 70 ml of methanol, and the mixture is heated at 50° C. for 6 h. The excess methanol and hydrochloric acid are stripped off in vacuo, and the solid residue is washed with methanol and dried in vacuo.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[NH:14][CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].[CH2:21]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Br)[CH2:22][CH2:23][C:24]#[CH:25].P([O-])([O-])([O-])=O>CN(C=O)C.O>[CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][O:26][CH2:21][CH2:22][CH2:23][C:24]#[CH:25])[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: C#CCCCOCCCCCCBr
Reactant: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCCCOCCCCCCN1C[C@@H](c2ccc3c(c2)COC(C)(C)O3)OC1=O
Reaction time: 0.17 h
Yield: 84 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (Example 1vi) (500 mg) in DMF (15 ml) under nitrogen at 0° was treated with sodium hydride (60% dispersion in mineral oil, 96 mg) and the mixture stirred at 20° for 10 min. A solution of 6-bromohexyl 4-pentyn-1-yl ether (WO 02/066422) (545 mg) in DMF (1 ml) was added and the mixture stirred at 20° for 18 h. Phosphate buffer solution (pH 6.5) and water were added and the mixture was extracted with EtOAc. The extract was washed with water and dried (Na2SO4). Solvent evaporation in vacuo gave a residue, which was purified by flash chromatography on silica gel. Elution with EtOAc-PE (2:3) gave the title compound (700 mg). LCMS RT=3.48 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15](O)=[O:16])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.CO>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:10][CH2:11][C@@H:12]([CH2:15][OH:16])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CO)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
cis-4-[(tert-Butoxy)carbonylamino]cyclohexane carboxylic acid (2.6 g, 10.68 mmol) was dissolved in THF (20 mL) and cooled to −10° C. (MeOH-ice). N-Methyl morpholine was added followed by isobutyl chloroformate (1.175 mL, 10.68 mmol). After 10 min, NaBH4 was added as a solid in one portion (1.213 g, 32.06 mmol). The reaction mixture was warmed to 0° C. and methanol was added dropwise (13.35 mL). After about 30 min, the reaction was quenched with 5% aqueous KHSO4. The reaction monitored by LC-MS was complete. The crude product was extracted with ethyl acetate and the combined extracts were dried over Na2SO4. A colorless oil was obtained and solidified slowly at room temperature. The product and purity were assessed by LC-MS and 1H NMR. No further purification was necessary. (quantitative yield) ES-MS (m/z) 230.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C@H:12]([CH:17]([CH3:19])C)[C:13]([O:15][CH3:16])=[O:14])[CH2:5]2.Br[C:21]1[CH:30]=[CH:29]C(C(OC)=O)=[C:23](CBr)[CH:22]=1.Cl.COC(=O)C(C1C=CC=CC=1)N>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C@@H:12]([CH2:17][C:19]1[CH:29]=[CH:30][CH:21]=[CH:22][CH:23]=1)[C:13]([O:15][CH3:16])=[O:14])[CH2:5]2
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2cc(Br)ccc2C1=O
Agent: COC(=O)C(N)c1ccccc1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)N1Cc2cc(Br)ccc2C1=O

Procedure:
The compound of example 380 was prepared analogous to compound of example 359 by reaction of the compound of example 358 and 2-phenyl glycine methyl ester hydrochloride.
Reaction SMILES: O=C([C@@:6]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([O:18][C:19](=[O:33])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])C([O-])=O.[C:42]([OH:45])(=[O:44])C>[Zn]>[CH2:35]([C@H:34]([CH:6]([O:18][C:19](=[O:33])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:42]([OH:45])=[O:44])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCCCCCCCCCCCCC(=O)O[C@](CCCCCCCCCCC)(CCc1ccccc1)C(=O)C(=O)[O-]
Reactant: CC(=O)O
Agent: [Zn]
Product: CCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCC)[C@@H](Cc1ccccc1)C(=O)O
Temperature: 115 °C
Yield: 86 %

Procedure:
Zinc dust (24.42 g, 373.3 mmol) was added to a solution of 46 (16.28 g, 28.42 mmol) in acetic acid (150 mL). The mixture was then heated to reflux (115° C.) for 3 h. The mixture was then concentrated in vacuo, and the residual pyridine removed by dissolving the residue in toluene (100 mL) and concentrating in vacuo. The resulting residue was by silica gel chromatography, eluting with a gradient of 0% through 30% ethyl acetate/hexanes to provide (R)-benzyl 3-(tetradecanoyloxy)tetradecanoic acid (47, 11.14 g, 86% yield) as a colorless oil. 1H NMR (CDCl3) δ 5.29-5.18 (m, 1H), 2.62-2.55 (m, 2H), 2.34-2.25 (m, 2H), 1.65-1.58 (m, 3H), 1.28-1.20 (m, 40H), 0.85 (m, 6H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[C:16]([O:20][C:21]([NH:23][C@H:24]([C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[CH2:25][C:26]1[C:31]([N+:32]([O-:34])=[O:33])=[CH:30][CH:29]=[C:28](O)[CH:27]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C.CC(C)=O.C(=O)=O>ClCCl.O>[C:16]([O:20][C:21]([NH:23][C@H:24]([C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[CH2:25][C:26]1[CH:27]=[C:28]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:29]=[CH:30][C:31]=1[N+:32]([O-:34])=[O:33])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(O)ccc1[N+](=O)[O-])C(=O)OCc1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(OS(=O)(=O)C(F)(F)F)ccc1[N+](=O)[O-])C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.0 ml (6.01 mmol) of trifluoromethanesulfonic anhydride is added dropwise to a solution of 2.27 g (5.46 mmol) of benzyl N-(tert-butoxycarbonyl)-3-hydroxy-6-nitro-L-phenylalaninate (Example 12I) and 1.52 ml (10.9 mmol) of triethylamine in 150 ml of dichloromethane at −15° C. (acetone/dry ice bath). After 15 min, the mixture is warmed to RT, and water is added. The organic phase is separated, washed several times with water, dried over magnesium sulfate and concentrated in vacuo. The crude product is purified by RP-HPLC (mobile phase: acetonitrile/water gradient).
Reaction SMILES: I[C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH2:10][CH2:11][N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[CH:33])=[N:30][CH:31]=2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[C:33][C:2]3[CH:18]=[CH:17][C:5]4[N:6]([CH2:10][CH2:11][N:12]5[CH2:16][CH2:15][CH2:14][CH2:13]5)[C:7](=[O:9])[NH:8][C:4]=4[CH:3]=3)=[N:30][CH:31]=2)=[CH:24][CH:25]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: O=c1[nH]c2cc(I)ccc2n1CCN1CCCC1
Product: O=c1[nH]c2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc2n1CCN1CCCC1

Procedure:
Prepared according to general working method I from 5-iodo-1-(2-pyrrolidin-1-yl-ethyl)-1,3-dihydro-benzimidazol-2-one (140 mg, 0.39 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (83 mg, 0.39 mmol).