Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[C@H:10]([CH3:11])[O:9]1.[N:18]1[N:19]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH:33]=[CH:32][NH:31][C:30]3=[O:34])=[CH:25][CH:24]=2)[N:20]=[N:21][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:9])([CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[C@H:10]([N:31]1[CH:32]=[CH:33][N:29]([C:26]2[CH:25]=[CH:24][C:23]([N:19]3[N:20]=[N:21][CH:22]=[N:18]3)=[CH:28][CH:27]=2)[C:30]1=[O:34])[CH3:11]
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccccc1F
Reactant: O=c1[nH]ccn1-c1ccc(-n2ncnn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: C[C@@H](n1ccn(-c2ccc(-n3ncnn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccccc1F
Temperature: 80 °C
Yield: 10.7 %

Procedure:
(2R,3S)-2-(2-Fluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (2.34 g), 1-[4-(2H-2-tetrazolyl)-phenyl]-2(1H,3H)-imidazolone (2.28 g) and cesium carbonate (powder: 6.52 g) were added to 1-methyl-2-pyrrolidone (100 ml), and the mixture was heated at 80° C. for 18 hours with stirring. The reaction solution was cooled, diluted with ethyl acetate (200 ml) and added to ice water (200 ml) to separate the ethyl acetate layer. The aqueous layer was extracted with ethyl acetate (100 ml). The combined ethyl acetate layers were washed with 1N-hydrochloric acid (100 ml×2) and a saturated aqueous solution of sodium chloride (100 ml) successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent:hexane/acetone=1/1) to give 1-[(1R,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2H-2-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (Compound 40; 0.494 g) as a colorless crystalline powder.
Reaction SMILES: [CH3:1][C:2]([C:7]1[S:11][C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:15][CH2:16][CH3:17])=[N:9][N:8]=1)([CH3:6])[CH2:3][CH:4]=O.[CH:31]([NH2:34])([CH3:33])[CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(Cl)Cl>[CH:31]([NH:34][CH2:4][CH2:3][C:2]([C:7]1[S:11][C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:15][CH2:16][CH3:17])=[N:9][N:8]=1)([CH3:6])[CH3:1])([CH3:33])[CH3:32]
Reactant: CC(C)N
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)CC=O)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)CCNC(C)C)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1,1-dimethyl-3-oxo-propyl)-[1,3,4]thiadiazol-2-yl]-amide (88 mg, 0.2 mmol), isopropylamine (0.09 ml) in dichloroethane (1 ml) and methylene chloride (1 ml) was stirred at r.t. for 10 min, sodium triacetoxyborohydride (76 mg) was added and the resulting mixture was stirred at r.t. overnight. The mixture was quenched with water, diluted with sodium hydroxide, and extracted with methylene chloride. The organic layer was separated, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography using 3-5% methanol in methylene chloride, then 5% methanol/0.5% ammonium hydroxide in methylene chloride as eluent to give the title compound as a free base form. The free base was treated with 4 N HCl in doxane (0.1 ml) in methylene chloride (1 ml) and concentrated to dryness. The residue was triturated with hexane, pumped to dryness to give a white solid, LC-MS RT=1.8 min, M+1=481.9.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].[CH3:6][O:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:23])[C:12]=2[C:11](OC)=[CH:10][CH:9]=1>C(Cl)Cl>[NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:11]1[C:12]2[C:13](=[O:23])[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20](=[O:22])[C:21]=2[C:8]([O:7][CH3:6])=[CH:9][CH:10]=1
Reactant: NCCCN
Reactant: COc1ccc(OC)c2c1C(=O)c1ccccc1C2=O
Solvent: ClCCl
Product: COc1ccc(NCCCN)c2c1C(=O)c1ccccc1C2=O

Procedure:
A solution of 1,3-diaminopropane (2.07 g, 28 mmol) and 1,4 dimethoxyanthraquinone (1.50 g, 5.6 mmol) in freshly distilled CH2Cl2 (1.5 l) was fitted with a reflux condenser, and irradiated with a sunlamp for 6 h. The solvent was distilled and the crude mixture was dried in vacuo overnight. The crude product was triturated with warm petroleum ether to remove excess amine. Chromatography (silica gel CCl4 and CH2Cl2, 1:1) was performed by slowly increasing the polarity of the solvent to CH2Cl2 to remove the unreacted 1,4-dimethoxyanthraquinone. Upon elution with methanol, a purple band slowly developed. A purple oil remained upon removal of the solvent. The oil was extracted with warm CCl4, and crystallized by adding petroleum ether to the combined CCl4 extracts. Crystallization afforded a purple solid, 0.48 g (28%) in three crops. Recrystallization from a mixture of CCl4 and petroleum ether afforded an analytical sample: mp 108°-110° C.; 1H NMR (CDCl3)δ9.95 (broad t, 1H), 8.21-8.25 (m, 2 H), 7.68-7.73 (m, 2 H), 7.37 (d, 1 H), 7.17 (d, 1H), 4.00(s, 3 H), 3.39-3.48 (m, 2 H), 2.94 (t,2 H), 1.86-1.98 (m, 2 H), 1.36 (broad s, 2H). Anal. Calcd. for C18H18N2O3 : C, 69.66; H, 5.85, N, 9.03. Found: C, 69.75; H 5.95; N, 8.95.
Reaction SMILES: [ClH:1].FC(F)(F)[C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[O:6][C@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.O[C@@H]1CCN(C(OC(C)(C)C)=O)C1.[Br:31]C1C=CC=CC=1O>>[ClH:1].[Br:31][C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[O:6][C@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1
Reactant: FC(F)(F)c1ccccc1O[C@H]1CCNC1
Reactant: Oc1ccccc1Br
Agent: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: Cl
Product: Brc1ccccc1O[C@H]1CCNC1

Procedure:
The title compound was prepared in the same manner as described for (3S)-3-[2-(trifluoromethyl)phenoxy]pyrrolidine hydrochloride from tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate and 2-bromophenol. 1H NMR (300 MHz, DMSO-d6): δ 7.60 (m, 1H), 7.35 (m, 1H), 7.18 (m, 1H), 6.94 (m, 1H), 5.18 (s, 1H), 3.53 (d, 1H), 3.32 (m, 3H), 2.14 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:14]=1.CC(C)([O-])C.[K+].Br[CH2:25][CH2:26][N:27]1[CH:31]=[CH:30][CH:29]=[CH:28]1.[I-].[K+]>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:25][CH2:26][N:27]3[CH:31]=[CH:30][CH:29]=[CH:28]3)[C:6]=2[N:14]=1
Reactant: BrCCn1cccc1
Reactant: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc2c3ccccc3n(CCn3cccc3)c2nc1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 70 mg, 0.310 mmol) in DMF (2 mL) was added potassium tert-butoxide (84 mg, 0.749 mmol). The reaction mixture was stirred at room temperature for 10 min, then 1-(2-bromoethyl)-1H-pyrrole (162 mg, 0.930 mmol) and potassium iodide (164 mg, 0.930 mmol) were added and the mixture was stirred at room temperature overnight. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (150 mL). The layers were separated and the organic layer was washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-3% methanol in methylene chloride gradient) to yield material which was subsequently triturated with ether to give pure 2-amino-9-[2-(1H-pyrrol-1-yl)ethyl]-9H-pyrido[2,3-b]indole-3-carboxamide as a white powder (20, 25 mg, 25%). NH4OAc standard conditions. DAD Retention time=6.79 min. M+H=320. 1H NMR (300 MHz, DMSO-d6): 8.71 (s, 1H), 7.97-7.89 (m, 1H), 7.79-7.69 (m, 1H), 7.67-7.50 (m, 2H), 7.24-7.04 (m, 4H), 6.62-6.59 (m, 2H), 5.88-5.82 (m, 2H), 4.57-4.47 (m, 2H), 4.34-4.24 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([OH:24])=[C:8]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][CH2:17][C:18]4=[O:23])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]([NH:35][CH2:36][CH2:37][CH3:38])=[O:34]>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][CH2:17][C:18]4=[O:23])[C:7]=2[O:24][CH2:32][C:33]([NH:35][CH2:36][CH2:37][CH3:38])=[O:34])[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OCC1CC1
Reactant: CCCNC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCNC(=O)COc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OCC1CC1
Temperature: 70 °C
Yield: 30.7 %

Procedure:
4-(3-(cyclopropylmethoxy)-2-hydroxy-4-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (100 mg, 0.308 mmol) in acetonitrile (15 mL) was added potassium carbonate (127 mg, 0.925 mmol) and 2-bromo-N-propylacetamide (110 mg, 0.616 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-45% ethyl acetate in pet ether) to afford the title compound as a solid (40 mg, 30.7%).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:51][CH2:52][CH:53]=[CH2:54])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2].C(N(CC)CC)C.[CH:65]1([C:68](Cl)=[O:69])[CH2:67][CH2:66]1>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:50][C:68]([CH:65]3[CH2:67][CH2:66]3)=[O:69])[CH:46]([O:51][CH2:52][CH:53]=[CH2:54])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2]
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1N
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1NC(=O)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 17-ethyl-1-hydroxy-12-[2'-(4"-amino-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in dry methylene chloride (0.4 ml) is cooled to 0° C. To this solution is added triethylamine (10 μl) followed by a solution of cyclopropane carbonyl chloride (5 mg) in methylene chloride (0.1 ml). The reaction mixture is stirred at 0° C. for 30 min. The reaction mixture is purified by preparative tlc on silica gel to give the title compound.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](Cl)(=[O:47])[O:9][C@@:10]([CH3:46])([C:13](=[O:45])[C@@H:14]([NH:22][C:23](=[O:44])[C@@H:24]([NH:28][C:29](=[O:43])[C@@H:30]([NH:34][C:35]([C:37]1[S:41][C:40]([CH3:42])=[N:39][CH:38]=1)=[O:36])[CH2:31][O:32][CH3:33])[CH2:25][O:26][CH3:27])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:11][I:12]>>[C:8](=[O:47])([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[O:9][C@@:10]([CH3:46])([C:13](=[O:45])[C@@H:14]([NH:22][C:23](=[O:44])[C@@H:24]([NH:28][C:29](=[O:43])[C@@H:30]([NH:34][C:35]([C:37]1[S:41][C:40]([CH3:42])=[N:39][CH:38]=1)=[O:36])[CH2:31][O:32][CH3:33])[CH2:25][O:26][CH3:27])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:11][I:12]
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@@](C)(CI)OC(=O)Cl
Reactant: Oc1ccccc1
Product: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@@](C)(CI)OC(=O)Oc1ccccc1

Procedure:
Prepared according to procedures described above, using phenol with the intermediate (2S,4S)-1-iodo-4-((S)-3-methoxy-2-((S)-3-methoxy-2-(2-methylthiazole-5-carboxamido)propanamido)propanamido)-2-methyl-3-oxo-5-phenylpentan-2-yl carbonochloridate. 1H NMR (CDCl3): δ 8.02 (s, 1H). 7.40 (t, J=8 Hz, 2H), 7.29-7.10 (m, 10H), 6.98 (d, J=7.2 Hz, 1H), 6.82 (d, J=6 Hz, 1H), 5.51-5.45 (m, 1H), 4.67-4.62 (m, 1H), 4.45-4.41 (m, 1H), 3.83-3.78 (m, 2H), 3.70-3.64 (m, 2H), 3.50 (t, J=4.8 Hz, 1H), 3.45 (s, 3H), 3.32-3.28 (m, 1H), 3.27 (s, 3H), 3.19-3.14 (m, 1H), 2.91-2.86 (m, 1H), 2.74 (s, 3H), 1.55 (s, 3H); MS for C32H37IN4O9S m/z: 782 (M+H)+.
Reaction SMILES: [CH2:1]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[O-2].[Zn+2:29].[C:30](=[S:32])=[S:31]>>[CH2:15]([N:14]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:30](=[S:31])[S-:32])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[Zn+2:29].[CH2:15]([N:14]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:30](=[S:31])[S-:32])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCCNCCCCCCCCCCCCC
Reactant: S=C=S
Agent: [O-2]
Agent: [Zn+2]
Product: CCCCCCCCCCCCCN(CCCCCCCCCCCCC)C(=S)[S-]
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a 250 mL round bottomed flask was placed 76.5 g of ditridecylamine and 8.10 g of zinc oxide. Carbon disulfide, 16.0 g, was then added dropwise, and the mixture was stirred for 30 minutes. The flask was then stirred and heated for 2 hours at 70° C., and then stirred for an addition 2 hours at 90° C. A vacuum was then applied to remove water of reaction and the temperature was increased to 130° C., and the reaction was maintained in this state for 3 hours. The pale yellow material was then filtered through Celite at 120° C., to give a pale yellow liquid with a Zn content of 5.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.C(N(CC)CC)C.F[B-](F)(F)F.BrC1C=CC=C[N+]=1CC>ClCCl>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=2)=[O:9])[C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][CH:3]=1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: O=C(O)c1cc(Cl)cnc1Oc1ccc(F)cc1
Agent: CC[n+]1ccccc1Br
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(CNC(=O)c2cc(Cl)cnc2Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.7 %

Procedure:
To a stirred solution of 5-chloro-2-(4-fluorophenoxy)nicotinic acid (150 mg, 0.56 mmol), methyl 4-(aminomethyl)benzoate hydrochloride (136 mg, 0.67 mmol), and triethylamine (0.31 mL, 2.24 mmol) in dichloromethane (8 mL) was added 2-bromo-1-ethylpyridinium tetrafluoroborate (230 mg, 0.84 mmol) at 0° C. The resulting mixture was warmed to room temperature and stirred for 16 h. The mixture was diluted with dichloromethane (50 mL) and washed with 1N hydrochloric acid (30 mL), saturated aqueous sodium hydrogen carbonate solution (30 mL), and brine (30 mL). The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (2:1) to afford 155 mg (67%) of the title compounds as white solids: 1H-NMR (CDCl3) δ 8.59 (1H, dd, J=2.6, 0.9 Hz), 8.26–8.17 (1H, m), 8.13 (1H, dd, J=2.8, 0.9 Hz), 8.00 (2H, d, J=8.1 Hz), 7.41 (2H, d, J=8.1 Hz), 7.15–7.07 (4H, m), 4.76 (2H, d, J=5.9 Hz), 3.90 (3H, s); MS (ESI) m/z 415 (M+H)+, 413 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[SH:12][C:13]1[N:14]([CH3:18])[CH:15]=[CH:16][N:17]=1>>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[S:12][C:13]1[N:14]([CH3:18])[CH:15]=[CH:16][N:17]=1
Reactant: Cn1ccnc1S
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Product: Cn1ccnc1Sc1c(Cl)cccc1[N+](=O)[O-]
Yield: 74.2 %

Procedure:
Starting with 1.92 g (10 mmoles) of 2,3-dichloronitrobenzene and 1.14 g (10 mmoles) of 2-mercapto-1-methylimidazole and following the procedure described in Example 1 there was obtained 2 g (74%) of the product as yellow prisms, mp 102°-104° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:6]([C:7]2[CH:12]=[C:11]([CH2:13]O)[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])=[CH:5][CH2:4][CH2:3]1.CN(C=O)C.S(Cl)([Cl:32])=O>C(Cl)Cl>[Cl:32][CH2:13][C:11]1[CH:10]=[CH:9][C:8]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])=[C:7]([C:6]2[C:2]([CH3:24])([CH3:1])[CH2:3][CH2:4][CH:5]=2)[CH:12]=1
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C2=CCCC2(C)C)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(CCl)cc2C2=CCCC2(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound T2.6 (1.10 g, 3.37 mmol) and a catalytic amount of DMF (0.10 mL) in DCM (12.0 mL), was slowly added thionyl chloride (0.802 g, 6.74 mmol) at 0° C. After addition, the reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the resulting residue was purified by CombiFlash®® silica gel column chromatography eluting with hexane/EtOAc, 100/0 to 95/5) to give the title compound T2 (1.15 g). 1H NMR (400 MHz, CDCl3) δ ppm. 7.32-7.39 (m, 2H), 7.28-7.29 (m. 1H), 6.88 (t, 1H), 6.80-6.82 (m, 2H), 5.56 (s, 1H), 4.66 (s, 2H), 3.78 (s, 3H), 2.27-2.29 (m, 2H), 1.69 (t, 2H), 0.89 (s, 6H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:11]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:12]=3[S:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:36]([OH:39])[C:37]#[CH:38]>O.[Cu]I.[Cu](I)I>[OH:39][CH2:36][C:37]#[C:38][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[C:11]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:12]=3[S:13][C:14]=2[C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(I)cc2)cc1
Reactant: C#CCO
Agent: I[Cu]I
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(C#CCO)cc2)cc1
Reaction time: 3 h

Procedure:
The product from Step 1 (214 mg, 0.43 mmol) was combined with triethylamine (35 mL), copper (I) iodide (0.4 mg), propargyl alcohol (50 mL, 0.86 mmol), bis-triphenylphosphine palladium dichloride at room temperature. The copper iodide was added last. The reaction was stirred for 3 hours then diluted with water and extracted into methylene chloride. The combined organic layers was dried over anhydrous magnesium sulfate. After filtration, concentration and silica gel column chromatography with 1.5% methanol-methylene chloride (gravity column) as eluant the title compound (195 mg) was obtained.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](OCC4C=CC=CC=4)=O)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:39]([O:44][CH2:45][C@@H:46]1[O:48]C1)(=[O:43])CCC>O1CCCC1>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:12][CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:24][C@H:45]([CH2:46][OH:48])[O:44][C:39]4=[O:43])=[CH:21][CH:22]=3)[CH2:15][CH2:16]2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCC(=O)OC[C@H]1CO1
Reactant: O=C(Nc1ccc(C2=CCN(C(=O)OCc3ccccc3)CC2)cc1)OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC=C(c2ccc(N3C[C@H](CO)OC3=O)cc2)CC1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of 3,6-dihydro-4-[4-[[(phenylmethoxy)carbonyl]amino]phenyl]-1(2H)-pyridinecarboxylic acid phenylmethyl ester (EXAMPLE 17, Step 2, 0.500 g) in dry tetrahydrofuran (5.7 mL) at -78° C. under N2 is treated with n-butyllithium (0.73 mL, 1.6M in hexanes) dropwise over five minutes. The resulting mixture is stirred at -78° C. for 45 minutes and is then treated with (R)-(-)-glycidyl butyrate dropwise. The resulting solution is allowed to warm to ambient temperature over approximately 45 minutes and is stirred for an additional 20 hours, after which the reaction is quenched with saturated aqueous ammonium chloride (10 mL), diluted with water (20 mL) and extracted with ethyl acetate (2×15 mL). The combined organic phase is washed with saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (230-400 mesh, 40 g), eluting with methanol/methylene chloride (1/99). Pooling and concentration of those fractions with an Rf =0.37 by TLC (methanol/chloroform, 5/95) gives the title compound, mp 131.5-133.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH2:28]>>[CH3:23][O:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH:28][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:15][CH:16]=1)=[O:22]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNC(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1

Procedure:
N-(2-Methoxybenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 2-methoxybenzylamine using method N. NMR; δH [2H6]—DMSO 8.95,(1H, t), 8.02,(2H, d), 7.90,(1H, dd), 7.77,(1H, d), 7.56-7.51,(3H, m), 7.26-7.19,(2H, m), 7.00,(1H, d), 6.91,(1H, t), 4.48,(2H, d), 3.83,(3H, s), 2.56,(3H, s), 2.32,(3H, s). LCMS; retention time 3.41 min, MH+ 414.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][NH:8][C:9](=[O:24])[CH:10]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([CH:21]=O)[C:15]=2[F:23])[O:11][CH2:12][CH3:13])=[CH:5][CH:4]=1)#[N:2].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[BH4-].[Na+]>CCO>[C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][NH:8][C:9](=[O:24])[CH:10]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([CH2:21][NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:15]=2[F:23])[O:11][CH2:12][CH3:13])=[CH:5][CH:4]=1)#[N:2]
Reactant: Nc1ccccc1
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(C=O)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(CNc2ccccc2)c1F
Temperature: 0 °C
Yield: 76.9 %

Procedure:
To a solution of (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-3-formyl-phenyl)-2-ethoxy-acetamide (250 mg, example 311.3) in EtOH (5 ml) was added aniline (64 mg). The suspension was stirred over night, then cooled to 0° C. and treated with NaBH4 (38 mg). The reaction mixture was stirred 1 h at 0° and 1 h at rt, then poured onto ice and extracted with EtOAc. The organic layer was dried over MgSO4, filtrated and concentrated. The crude product was purified by flash chromatography (cyclohexane/EtOAc 1:4=>EtOAc) to give (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-3-phenylaminomethyl-phenyl)-2-ethoxy-acetamide (230 mg) as off-white amourphous solid. MS 436.3 ([M+H]+)