Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[N+:15]([O-])=O>[Cl-].[NH4+].CO.[Fe]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[NH2:15]
Reactant: CN1CCN(c2ccc(Br)c([N+](=O)[O-])c2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CN1CCN(c2ccc(Br)c(N)c2)CC1
Yield: 68.4 %

Procedure:
A suspension of iron powder (1.77 g, 31.6 mmol) in saturated aqueous ammonium chloride solution (140 ml) at 100° C., was treated dropwise with a solution of 1-(4-bromo-3-nitrophenyl)-4-methylpiperazine (D26) (3.54 g, 11.8 mmol) in methanol (70 ml). The mixture was refluxed for a further 1 h, and was then cooled and partitioned between water and 3% methanol in dichloromethane. The organic phase was dried (Na2SO4) and evaporated under reduced pressure to give the crude product. This was purified by chromatography on silica gel, eluting with methanol and dichloromethane to give the title compound (D27) as a white solid (2.18 g, 68%) MH+=270/272.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:11]2[N:12]([CH2:16][C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])[C:13](=[O:15])[NH:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].N(C(C)(C)C#N)=NC(C)(C)C#N.[Cl:35]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>ClC1C=CC=CC=1>[Cl:35][C:9]1[C:10]2[NH:14][C:13](=[O:15])[N:12]([CH2:16][C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])[C:11]=2[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][CH:8]=1
Reactant: CCC(CC)c1cccc2[nH]c(=O)n(CC(=O)OC(C)C)c12
Reactant: O=C1CCC(=O)N1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Clc1ccccc1
Product: CCC(CC)c1ccc(Cl)c2[nH]c(=O)n(CC(=O)OC(C)C)c12
Temperature: 70 °C
Reaction time: 84 h
Yield: 75.3 %

Procedure:
To a solution of isopropyl [7-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate (17.9 g, 58.8 mmol) and 2,2′-azobisisobutyronitrile (966 mg, 5.88 mmol) in chlorobenzene (170 mL) was added portionwise N-chlorosuccinimide (7.85 g, 58.8 mmol) at 65° C., and the mixture was stirred at 70° C. for 3.5 days. After cooling, the reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate (200 mL), and the aqueous layer was separated and extracted with ethyl acetate (200 mL). The combined organic layer was washed with aqueous sodium chloride (200 mL) and brine (150 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 15-25% ethyl acetate/n-hexane gradient mixture to give the title compound (15.0 g, 44.3 mmol, 75.3%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16])=[CH:4][C:3]=1[S:23]([NH:26][CH2:27][O:28][C:29](=[O:38])[CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36]C)=[O:35])(=[O:25])=[O:24].[C-]#N.[Na+]>CN(C)P(N(C)C)(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16])=[CH:4][C:3]=1[S:23]([NH:26][CH2:27][O:28][C:29](=[O:38])[CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])(=[O:25])=[O:24]
Reactant: COC(=O)CCCCC(=O)OCNS(=O)(=O)c1cc(C(=O)OCC(Cl)(Cl)Cl)c(NCc2ccco2)cc1Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(O)CCCCC(=O)OCNS(=O)(=O)c1cc(C(=O)OCC(Cl)(Cl)Cl)c(NCc2ccco2)cc1Cl
Temperature: 75 °C
Reaction time: 24 h

Procedure:
A mixture of methyl 6-(2-chloro-4-[(2-furanylmethyl)amino]-5-(2,2,2-trichloroethoxycarbonyl)phenylsulfonamidomethoxy)(6-oxo)hexanoate (0.060 mole), sodium cyanide (0.060 mole) and hexamethylphosphoramide (Aldrich) (100 mL) is stirred at 75° C. for 24 hours. The volatiles are removed by spin evaporation in vacuo. The residue is dissolved in cold water, and the solution is washed with diethyl ether. The aqueous solution is cooled in an ice bath and acidified by dropwise addition of 1.0 N hydrochloric acid solution (60 mL). The resulting solid may be collected and recrystallized to give 6-(2-chloro-4-[(2-furanylmethyl)amino]-5-(2,2,2-trichloroethoxycarbonyl)phenylsulfonamidomethoxy)(6-oxo)hexanoic acid. See Greene et al., Protective Groups in Organic Synthesis, Second Edition, (1991) p. 232.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:29][CH2:30][C:31](N)=[O:32])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:42])C=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:29][CH2:30][C:31]([OH:32])=[O:42])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(-c2cccnc2)cc1)N1CC[C@](CCC(N)=O)(c2ccc(F)cc2)OC1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C[C@@H](c1ccc(-c2cccnc2)cc1)N1CC[C@](CCC(=O)O)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 13.9 %

Procedure:
To a solution of 3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-6-yl) propanamide (70 mg, 0.16 mmol) in CH2Cl2 (10 mL), was added m-CPBA (135 mg, 0.79 mmol), and the reaction mixture was stirred at rt for 3 h. After the solvent was removed under reduced pressure, the residue was purified by preparative TLC to afford 3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanoic acid (10 mg, 15%). LC-MS Method 2 tR=0.987 min, m/z=464.17; 1H NMR (CDCl3): 1.51 (m, 3H), 1.92 (m, 1H), 2.12-2.28 (m, 5H), 2.43 (m, 1H), 2.95 (m, 1H), 5.56 (m, 1H), 5.65 (m, 1H), 5.31 (m, 1H), 6.95 (m, 2H), 7.08 (m, 2H), 7.15 (m, 1H), 7.20 (m, 1H), 7.25 (m, 2H), 7.56 (m, 1H), 7.24 (m, 1H), 8.35 (m, 1H), 8.65 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.Cl[Si:10]([CH2:17][CH2:18][CH3:19])([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13]>>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Si:10]([CH2:17][CH2:18][CH3:19])([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[CH:3]=1
Reactant: Brc1cccc(Br)c1
Reactant: CCC[Si](Cl)(CCC)CCC
Product: CCC[Si](CCC)(CCC)c1cccc(Br)c1

Procedure:
1-Bromo-3-tri-n-propylsilanyl-benzene is prepared in a manner analogous to the procedure described in examples 1 and 1a utilizing 1,3-dibromobenzene and chloro-tri-n-propylsilane as the ClSiR1R2R3 compound.
Reaction SMILES: C([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[CH:17]=[C:16]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:15]=[CH:14][C:13]=3[NH:12][C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:29]>C(O)C.[Pd]>[ClH:29].[O:22]([C:16]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[CH2:10][CH2:9][NH:8][CH2:21][CH2:20][C:19]=3[C:18]=2[CH:17]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: c1ccc(CN2CCc3[nH]c4ccc(Oc5ccccc5)cc4c3CC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1ccc(Oc2ccc3[nH]c4c(c3c2)CCNCC4)cc1
Yield: 86.7 %

Procedure:
A solution of 3-benzyl-9-phenoxy-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indole (0.092 g, 0.26 mmol) in ethanol (20.0 mL) was hydrogenated in the presence of palladium on carbon (0.04 g) and 2 N hydrochloric acid (0.13 mL, 0.26 mmol,) at 50 psi for 16 h. After filtration through a pad of Celite, the filtrate was concentratec in vacuo to dryness. The residue was recrystalized from EtOAc/MeOH to give 0.071 g (99%) of colorless solid as the desired product: mp>227° C. (dec.); 1H NMR (400 MHz, DMSO-d6) δ 11.10, 9.60, 7.32-7.28, 7.11, 7.01, 6.88, 6.77, 3.36-3.27, 3.21-3.19, 3.05-3.01; 13C NMR (100.6 MHz, DMSO-d6) δ 159.1, 148.5, 136.4, 131.5, 129.6, 128.5, 121.7, 116.6, 114.0, 111.8, 109.7, 108.1, 46.6, 44.8, 24.7, 20.8; MS (EI) m/z 278 (M+); HRMS cacld for C18H18N2O+H: 279.1497, found: 279.1508; Anal. Calcd. for C18H18N2O.HCl: C, 68.67; H, 6.08; N, 8.90. Found: C, 67.95; H, 6.14; N, 8.99.
Reaction SMILES: [Li].[CH3:2][C:3]1[CH2:8][C@@H:7]([C:9](OC)=[O:10])[C@H:6]([C:13](OC)=[O:14])[CH2:5][C:4]=1[CH3:17].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[OH:10][CH2:9][C@H:7]1[C@H:6]([CH2:13][OH:14])[CH2:5][C:4]([CH3:17])=[C:3]([CH3:2])[CH2:8]1
Reactant: COC(=O)[C@@H]1CC(C)=C(C)C[C@H]1C(=O)OC
Agent: O=S(=O)([O-])[O-]
Agent: [Li]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=C(C)C[C@@H](CO)[C@H](CO)C1
Yield: 36 %

Procedure:
To a suspension of lithium alumium hydride (1.529 g, 0.04 mol) in dry THF (60 ml) at 0° C. was added trans-dimethyl 1,2-dimethylcyclohex-1-ene-4,5-dicarboxylate (2.269 g, 0.01 mol) in dry THF (40 ml) over 30 min. The resultant suspension was stirred for another hour at 0° C., and then saturated sodium sulphate solution (5ml) was added dropwise. The solution was filtered and the filtrate evaporated to give an oil, which on purification gave the title compound in 36% yield. N.m.r: δH (90 MHz, CDCl3) 3.70 (m,4H), 3.55 (bs,2H), 2.02 (m,4H), 1.96 (m,2H), 1.64 ppm (s,6H).
Reaction SMILES: O=[C:2]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[O:16][CH3:17])[C:3]([OH:5])=[O:4].[CH3:18][NH2:19].C(O)(=O)C.[ClH:24]>C(O)C.[Pd]>[ClH:24].[CH3:18][NH:19][CH:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[O:16][CH3:17])[C:3]([OH:5])=[O:4]
Reactant: COc1cccc(C=CC(=O)C(=O)O)c1OC
Reactant: CN
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CNC(CCc1cccc(OC)c1OC)C(=O)O
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
70.0 g of 2-keto-4-(2,3-dimethoxyphenyl)-3-butenoic acid (0,30 moles) dissolved in 700 ml of ethanol are placed into a hydrogenator, then 43.0 g of an 8.03M (0.34 mole) methylamine solution and glacial acetic acid under nitrogen atmosphere are added to pH from 8 to 9, keeping the temperature below 25° C. Stirring is continued for about 15 minutes, then 14.0 g of 5% Pd/C (about 50% humidity) are added, under hydrogen pressure (40 psi, room temperature) for 6 hours. The reaction mixture is then adjusted to markedly acid pH with concentrated HCl, filtered and the solution is evaporated to dryness. The resulting solid is taken up and triturated with heating (50° C.) with 300 ml of acetone, then it is left to cool under stirring, filtered and dried under vacuum at 40° C. Yield: 51 g, 60% (moles), 73%(weight); TLC: methylene chloride/methanol/acetic acid 75/20/10; Rf=0,5; Developer: ninhydrin. M.p.=165°-166° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:32][N:33]1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43].[CH2:44]([O:51][C:52]1[C:53](=[O:60])[CH:54]=[C:55]([CH2:58]O)[O:56][CH:57]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>O1CCCC1>[CH2:44]([O:51][C:52]1[C:53](=[O:60])[CH:54]=[C:55]([CH2:58][O:32][N:33]2[C:34](=[O:43])[C:35]3=[CH:42][CH:41]=[CH:40][CH:39]=[C:36]3[C:37]2=[O:38])[O:56][CH:57]=1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=c1cc(CO)occ1OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCc1cc(=O)c(OCc2ccccc2)co1
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.4 %

Procedure:
Diethyl azodicarboxylate (16.68 g) (86 mmol) are dissolved in 1200 ml of absolute tetrahydrofuran. Thereto there is added a mixture consisting of 22.6 g (86 mmol) of triphenylphosphine, 14.1 g (86 mmol) of N-hydroxyphthalimide and 20.0 g (86 mmol) of 5-(benzyloxy)-2-(hydroxymethyl)-4H-pyran-4-one (known from J. Med. Chem. 17, 1, 1974). After stirring at room temperature for 20 hours the mixture is filtered and the filter material is rinsed with ethanol. The filtrate and rinse solution are combined and concentrated, and the residue is crystallized using ethanol. After repeated recrystallization from ethanol there are obtained 23.5 g of N-[[5-(benzyloxy)-4-oxo-4H-pyran-2-yl]methoxy]phthalimide as white crystals of m.p. 172° C.
Reaction SMILES: [F:1][CH:2]([F:8])[CH2:3][S:4](Cl)(=[O:6])=[O:5].[OH:9][C@:10]([CH3:46])([CH2:44][OH:45])[C:11](=[O:43])[C@@H:12]([NH:20][C:21](=[O:42])[C@@H:22]([NH:26][C:27](=[O:41])[C@@H:28]([NH:32][C:33]([C:35]1[S:39][C:38]([CH3:40])=[N:37][CH:36]=1)=[O:34])[CH2:29][O:30][CH3:31])[CH2:23][O:24][CH3:25])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[F:1][CH:2]([F:8])[CH2:3][S:4]([O:45][CH2:44][C@:10]([OH:9])([CH3:46])[C:11](=[O:43])[C@@H:12]([NH:20][C:21](=[O:42])[C@@H:22]([NH:26][C:27](=[O:41])[C@@H:28]([NH:32][C:33]([C:35]1[S:39][C:38]([CH3:40])=[N:37][CH:36]=1)=[O:34])[CH2:29][O:30][CH3:31])[CH2:23][O:24][CH3:25])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:6])=[O:5]
Reactant: O=S(=O)(Cl)CC(F)F
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)(O)CO
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)(O)COS(=O)(=O)CC(F)F

Procedure:
Prepared according to procedures described above, by reacting 2,2-difluoroethanesulfonyl chloride with N—((S)-1-(((S)-1-(((2S,4R)-4,5-dihydroxy-4-methyl-3-oxo-1-phenylpentan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide. MS for C27H36F2N4O10S2 m/z: 679 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=O)[C:4]([N+:9]([O-:11])=[O:10])=[N:3]1.[C:12]([NH2:18])(=[O:17])[CH2:13][C:14]([OH:16])=[O:15]>N1C=CC=CC=1>[C:12]([C:13](=[CH:7][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[N:3][N:2]([CH3:1])[CH:6]=1)[C:14]([OH:16])=[O:15])(=[O:17])[NH2:18]
Reactant: NC(=O)CC(=O)O
Reactant: Cn1cc(C=O)c([N+](=O)[O-])n1
Solvent: c1ccncc1
Product: Cn1cc(C=C(C(N)=O)C(=O)O)c([N+](=O)[O-])n1

Procedure:
When the reaction of 1-methyl-3-nitropyrazole-4-aldehyde and malonic acid monoamide in pyridine is carried out at 70° C., then, as intermediate product, there can be isolated 2-carbamoyl-3-(1-methyl-3-nitro-4-pyrazolyl)-acrylic acid. For decarboxylation, 0.1 g. of this product is stirred in 1 ml. pyridine for 1.5 hours at a bath temperature of 120° C. The reaction mixture is then cooled, ice-cold semi-concentrated hydrochloric acid is added thereto and the precipitated crystals are filtered off with suction, washed with water and dried. There is obtained 0.02 g. 3-(1-methyl-3-nitropyrazolyl)-acrylamide.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][C:5]12[CH2:12][CH2:11][C:8]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][C:26]5[O:27][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[N:29][N:30]=5)=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)([CH2:9][CH2:10]1)[O:7][CH2:6]2.O.[OH-].[Li+]>O1CCCC1.C(O)C.O>[C:31]([C:28]1[O:27][C:26]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([C:16]3[CH:17]=[CH:18][C:13]([C:8]45[CH2:9][CH2:10][C:5]([CH2:4][C:3]([OH:35])=[O:2])([CH2:12][CH2:11]4)[CH2:6][O:7]5)=[CH:14][CH:15]=3)=[CH:24][CH:23]=2)=[N:30][N:29]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: COC(=O)CC12CCC(c3ccc(-c4ccc(Nc5nnc(C(C)(C)C)o5)cc4)cc3)(CC1)OC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1nnc(Nc2ccc(-c3ccc(C45CCC(CC(=O)O)(CC4)CO5)cc3)cc2)o1
Temperature: 50 °C
Yield: 71.6 %

Procedure:
A 100 ml round bottom flask was charged with {1-[4′-(5-tert-butyl-[1,3,4]oxadiazol-2-ylamino)-biphenyl-4-yl]-2-oxa-bicyclo[2.2.2]oct-4-yl}-acetic acid methyl ester (0.27 g, 0.454 mmol), and lithium hydroxide monohydrate (0.229 g, 5.45 mmol) in tetrahydrofuran (20 ml), ethanol (10 ml) and water (8 ml) at room temperature. The mixture was heated at 50° C. for 2 hours. Most of the organic solvent was evaporated under vacuum and the mixture was acidified to PH=4 at 0° C. The solvents were then removed by lipherlizer. The mixture was added ethanol (40 ml) and heated to 70° C., and then was cooled to room temperature. The mixture was filtered and the solid was washed with ethanol (3 ml) and water (10 ml) to afford {1-[4′-(5-tert-butyl-[1,3,4]oxadiazol-2-ylamino)-biphenyl-4-yl]-2-oxa-bicyclo[2.2.2]oct-4-yl}-acetic acid (150 mg, 71%) as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.64-1.89 (m, 6H) 2.00-2.13 (m, 4H) 3.85 (s, 2H) 7.42 (d, J=8.40 Hz, 2H) 7.55 (d, J=8.50 Hz, 2H) 7.62 (s, 4H) 10.46 (br. s, 1H). LC/MS, [MS+] 461.23, RT: 2.66 (Condition M).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O[N:19]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[OH-].[NH4+]>ClCCl.O>[C:14]([C@@H:11]1[CH2:12][CH2:13][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10]1)(=[O:16])[NH2:19]
Reactant: CC(C)(C)OC(=O)NC1CCC(C(=O)O)C1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(N)=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.8 %

Procedure:
To a solution of racemic (1R,3S)-3-(tert-butoxycarbonylamino)cyclopentane-carboxylic acid (AMRI, 3.9 g, 17.0 mmol) in dichloromethane (100 mL) was added 1-hydroxybenzotriazole monohydrate (3.1 g, 20.4 mmol), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (4.7 g, 24.7 mmol) and ammonium hydroxide (19.9 g, 170 mmol). The reaction mixture was stirred at room temperature for 16 h and then diluted with water (20 mL). The aqueous layer was extracted with dichloromethane (3×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated in 50 mL of 1:1 ethyl acetate/hexanes and collected by filtration to obtain 1.7 g of the title compound. MS (ESI+) M/Z 228 [M+H]+.
Reaction SMILES: [CH2:1]([S:9]([CH2:12][C:13]([O:15]C)=O)(=[O:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[NH4+:18]>CO>[CH2:1]([S:9]([CH2:12][C:13]([NH2:18])=[O:15])(=[O:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: [NH4+]
Reactant: CCCCCCCCS(=O)(=O)CC(=O)OC
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCS(=O)(=O)CC(N)=O
Reaction time: 24 h

Procedure:
A solution of methyl n-octanesulphonylacetate (35 g, 0.143 mole) in 350 ml of anhydrous methanol was stirred magnetically at room temperature. To this solution was added 24 ml of aqueous ammonium hydroxide (27%, 6.48 g, 0.185 mole) in drops over a period of 30 minutes. The solution was stirred for 24 h and the white precipitate formed was filtered. The solid was recrystallized from hot ethyl acetate to obtain the required acetamide III-50 as a crystalline solid, mp. 140-142° C., 33 g, 97.6%.
Reaction SMILES: [F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[C:16]2[CH:25]=[C:24](C(OCC)=O)[NH:23][C:17]=2[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=1.C[Mg]Br.Cl.O1C[CH2:43][CH2:42][CH2:41]1>>[F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[C:16]2[CH:25]=[C:24]([C:42]([CH3:43])=[CH2:41])[NH:23][C:17]=2[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)c1cc2c(-c3cc(S(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c(=O)c2[nH]1
Agent: C[Mg]Br
Agent: Cl
Product: C=C(C)c1cc2c(-c3cc(S(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c(=O)c2[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
To a solution of Example 252f (0.10 g, 0.20 mmol) in tetrahydrofuran (6 mL) stirring at 0° C. was added methylmagnesium bromide (0.498 mL, 0.498 mmol). The reaction mixture was stirred at 0° C. for 1 hour, and then aqueous HCl (1 M, 2 mL) was added. The reaction mixture was concentrated and partitioned between saturated aqueous sodium chloride (10 mL) and ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase-HPLC (C 18 40-90% gradient acetonitrile:water (0.1% TFA)) to provide the title compound (25 mg, 25% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.05 (s, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.87 (dd, J=8.7, 2.4 Hz, 1H), 7.61-7.36 (m, 3H), 7.18 (t, J=8.6 Hz, 1H), 6.98 (d, J=8.3 Hz, 1H), 6.34 (d, J=2.2 Hz, 1H), 5.85 (s, 1H), 5.07 (s, 1H), 3.60 (s, 3H), 3.26 (s, 3H), 2.02 (s, 3H). MS (ESI+) m/z 471.1 (M+1)+.
Reaction SMILES: [Cl-].[NH3+:2][C:3]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH:17]([O-])=O.[Na+]>C(O)=O>[CH:17]1[N:15]2[C:16]3[C:3](=[CH:4][CH:5]=[CH:6][C:7]=3[O:8][C:9]3[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:2]=1
Reactant: [NH3+]c1cccc2c1Nc1ccccc1O2
Reactant: O=C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O=CO
Product: c1ccc2c(c1)Oc1cccc3ncn-2c13
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
18.45 g (78.6 mmol) of 1-ammoniophenoxazine chloride are suspended in 85 ml of 85% strength formic acid. After addition of 5.38 g (78.6 mmol) of sodium formate, the reaction mixture is refluxed for 3.5 hours. After cooling to room temperature, the reaction mixture is precipitated in 700 g of 10% strength NaOH and stirred for another 30 minutes. The solid is filtered off with suction on a “black band” filter, washed with water and dried at 70° C. under reduced pressure. The crude product (16.35 g) is stirred in 160 ml of methanol for 2 hours, subsequently filtered off with suction, washed with methanol and dried at 70° C. This gives 13.09 g (80% of theory) of gray needles which melt at 177-181° C. (lit.: 177-178° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:10](Cl)(=[O:12])=[O:11])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[CH2:14]([O:16][C:17](=[O:29])[CH:18]([NH2:28])[CH:19]([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])[CH3:15].N1C=CC=CC=1>C(Cl)Cl>[CH2:14]([O:16][C:17](=[O:29])[CH:18]([NH:28][S:10]([C:4]1[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=1)(=[O:12])=[O:11])[CH:19]([C:20]([F:23])([F:21])[F:22])[C:24]([F:26])([F:27])[F:25])[CH3:15]
Reactant: O=S(=O)(Cl)c1cc(F)c(F)c(F)c1
Reactant: CCOC(=O)C(N)C(C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(NS(=O)(=O)c1cc(F)c(F)c(F)c1)C(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Yield: 84.3 %

Procedure:
A solution of 3,4,5-trifluorobenzenesulfonyl chloride (0.348 mL, 2.50 mmol) in CH2Cl2 (5 mL) was added to a solution of 2-amino-4,4,4-trifluoro-3-trifluoromethyl-butyric acid ethyl ester (0.4 g, 1.67 mmol) prepared as described (J. Med Chem. 1981, 24, 1043-1047), and pyridine (0.27 mL, 3.34 mmol) in CH2Cl2 (5 mL) at 0° C. and allowed to warm to 25° C. for 19 h. The solution was washed with 1M HCl (1 mL), brine (1 mL), dried over Na2SO4 and concentrated. The crude solid was purified by Biotage Flash™ chromatography, eluting with EtOAc/hexanes (1:4), to give 4,4,4-trifluoro-2-(3,4,5-trifluoro-benzenesulfonylamino)-3-trifluoromethyl-butyric acid ethyl ester (0.63 g, 85%) as a white solid. Mass Spectrum (+ESI): 448 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7](Cl)=[O:8].Cl.[CH3:11][NH:12][O:13][CH3:14].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:14][O:13][N:12]([CH3:11])[C:7]([C:6]1[O:5][CH:4]=[N:3][C:2]=1[CH3:1])=[O:8]
Reactant: CNOC
Reactant: Cc1ncoc1C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ocnc1C
Temperature: 25 °C

Procedure:
4-Methyl-5-oxazolecarbonyl chloride (15g) and N,O-dimethylhydroxylamine hydrochloride (11 g) in dry chloroform (looml) were cooled to OOC and dry pyridine (28.5g) was added. The mixture was allowed to warm to room temperature. After 30 minutes aqueous sodium hydrogen carbonate was added and the organic layer separated. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed, dried and evaporated. The residue was purified by flash chromatography to yield the title compound as a white solid. M.p. 59®-60° C. 1H Nmr (CDC3) 2.5, 3.34 and 3.82 (each 3H, s) and 7.86 (1H, S) ppm. Found: C, 49.0; H, 5.6; N, 16.4. C7H10N2O3 requires C, 49.4; H, 5.9; N, 16.5%