Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:14])[C:9](=O)[CH2:10][C:11]#[N:12])[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.[NH2:22][OH:23]>C(O)C.N1C=CC=CC=1>[NH2:12][C:11]1[O:23][N:22]=[C:9]([CH:8]([C:6]2[CH:5]=[CH:4][C:3]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:2]([F:1])[CH:7]=2)[CH3:14])[CH:10]=1
Reactant: CC(C(=O)CC#N)c1ccc(-c2ccccc2)c(F)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1cc(N)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To 4-(2-Fluoro-4-biphenylyl)-3-oxo-pentanenitrile (2.75 g, 10.3 mmol) in ethanol (70 ml) was added hydroxylamine hydrochloride (1.1 g, 15.8 mmol) in pyridine (10 ml). After addition, the mixture was stirred at room temperature overnight, then evaporated under reduced pressure to a residue, which was chromatographed and then recrystalyzed to afford 5-amino-3-(1-(2-fluoro-4-biphenylyl)ethyl)isoxazole (2.20 g, 76% yield) as crystalline material: mp 122°-123° C.
Reaction SMILES: [CH:1]([N:4]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:7](=[O:21])[C:6]([C:22](O)=[O:23])=[CH:5]1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][CH2:59][C:60]1[CH:65]=[CH:64][C:63]([S:66](=[N:71][CH3:72])([N:68]([CH3:70])[CH3:69])=[O:67])=[CH:62][CH:61]=1>CN(C=O)C.O>[CH3:69][N:68]([CH3:70])[S:66]([C:63]1[CH:64]=[CH:65][C:60]([CH2:59][NH:58][C:22]([C:6]2[C:7](=[O:21])[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:20])[F:19])[CH:12]=3)=[C:9]([CH3:10])[N:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=2)=[O:23])=[CH:61][CH:62]=1)(=[N:71][CH3:72])=[O:67]
Reactant: CN=S(=O)(c1ccc(CN)cc1)N(C)C
Reactant: Cc1c(-c2cccc(C(F)(F)F)c2)c(=O)c(C(=O)O)cn1C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN=S(=O)(c1ccc(CNC(=O)c2cn(C(C)C)c(C)c(-c3cccc(C(F)(F)F)c3)c2=O)cc1)N(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 1-isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carboxylic acid (preparation 9.2, 186 mg, 0.55 mmol) in DMF (5 mL) is treated with DIPEA (300 μL, 1.72 mmol) and stirred at room temperature for 10 min. HBTU (312 mg, 0.82 mmol) is added, and the mixture is stirred for 20 min. A solution of 4-(aminomethyl)-N,N,N′-trimethylbenzenesulfonimidamide (preparation 60d, 156 mg, 0.69 mmol) in DMF (0.5 mL) is added and the mixture is stirred for 2 h. Water is added and the mixture is extracted with dichloromethane. The organic layer is dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by preparative reversed phase HPLC (Xbridge, gradient of acetonitrile in water, 0.1% TFA). Yield: 41 mg (11% of theory); ESI mass spectrum: [M+H]+=549; r.t. HPLC: 1.17 min (Z001_005).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O[CH2:10][CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:21]1COCC1>C1N2CCN(CC2)C1>[C:11]([CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:21])=[CH:4][CH:3]=1)#[CH:10]
Reactant: Nc1ccccc1
Reactant: C1CCOC1
Reactant: O=C([O-])OCC=Cc1ccccc1
Agent: C1CN2CCN1CC2
Product: C#CC(Nc1ccc(C)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 80 %

Procedure:
A typical procedure is given for the reaction of entry 1 in Table 1. In a drybox, DABCO (5.6 mg, 0.050 mmol), [Ir(cod)Cl]2 (3.4 mg, 0.005 mmol) and (Ra,Rc,Rc)-7 (6.4 mg, 0.01 mmol) were dissolved in 0.5 mL of THF in a screw-capped vial. A small magnetic stirbar was added, and the vial were sealed with a cap containing a PTFE septum and removed from the drybox. Aniline (130 mg, mmol) and cinnamyl carbonate (188 mg, 0.979 mmol) were added to the reaction mixture by syringe. The reaction mixture was stirred at room temperature for 10 h and monitored by GC and TLC. After the reaction was complete, the volatile materials were evaporated. 1H NMR analysis of the residue crude mixture indicated the ratio of regioisomers to be greater than 99/1. The mixture was then purified by flash column chromatography on silica gel (1.5% ethyl acetate in hexanes) to give the desired α-Ethynyl-N-(p-tolyl)-benzenemethanamine (0.164 g, 80%). HPLC analysis indicated that the enantiomeric excess of the product was 95% [Diacel CHIRALCEL OD-H (0.46 cm×25 cm); hexanes/2-propanol=99.75/0/25; flow rate=0.6 mL/min; detection wavelength=254 nm; Tr=(major), (minor) min]. α-Ethynyl-N-phenylbenzenemethanamine. 1H NMR (400.13 MHz, CDCl3) δ 7.44-7.24 (m, 5H), 7.20-7.10 (m, 2H), 6.69 (t, J=7.2 Hz, 1H), 6.60 (d, J=8.0 Hz, 2H), 6.04 (ddd, J=16.8, 10.4, 6.4 Hz, 1H), 5.28 (dt, J=17.2, 1.2 Hz, 1H), 5.22 (dt, J=10.0, 1.2 Hz, 1H), 4.94 (t, J=4.4 Hz, 1H), 4.04 (br s, 1H).
Reaction SMILES: C(#N)C.[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH:12][CH:13]=[O:14])=[CH:7][CH:6]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][C:17]=1[N+:26]([O-:28])=[O:27].[Cl-].[Na+]>CN(C)C(=O)C.N1C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:4][C:5]2[CH:6]=[CH:7][C:8]([NH:11][NH:12][CH:13]=[O:14])=[CH:9][CH:10]=2)(=[O:24])=[O:23])=[CH:18][C:17]=1[N+:26]([O-:28])=[O:27]
Reactant: Nc1ccc(NNC=O)cc1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: O=CNNc1ccc(NS(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)cc1
Temperature: -5 °C
Yield: 77.8 %

Procedure:
In a mixture of 90 ml of N,N-dimethylacetamide, 76 ml of acetonitrile, and 19 ml of pyridine were dissolved 35.4 g of 2-(4-aminophenyl)-1-formylhydrazine in a nitrogen gas atmosphere and after cooling the solution to -5° C., 59.9 g of 4-chloro-3-nitrobenzenesulfonyl chloride were gradually added to the solution while cooling and with stirring so that the liquid temperature was not over -5° C. After further stirring the mixture for 1.5 hours at a temperature below -5° C., the temperature was raised to room temperature and the reaction mixture was poured into 1 liter of a saturated aqueous sodium chloride solution. Crystals thus formed were collected by filtration and washed with water to provide 67.5 g of the desired compound.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:2].C([Sn]([N:24]=[N+:25]=[N-:26])(CCCC)CCCC)CCC.Cl>COCCOC.CO>[NH:24]1[C:1]([CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N:2][N:26]=[N:25]1
Reactant: CCOC(=O)CCCC#N
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: Cl
Solvent: COCCOC
Solvent: CO
Product: CCOC(=O)CCCc1nnn[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 4-cyanobutyrate (approximately 15 g) was dissolved in DME. Tris(n-butyl)tin azide (5 ml) was added and the reaction solution was heated to 85° overnight then cooled to room temperature. The cooled solution was diluted with methanol (20 ml) then 1N hydrochloric acid (20 ml) was added. The solution was stirred for one hour then partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed by preparatory-scale HPLC (silcia column) eluted with a gradient of 30 to 70% ethyl acetate in hexane plus 1% acetic and to yield 3.39 g of the title product: n.m.r.(300 MHz, CDCl3) δ: 4.2 (q, 2H); 2.95 (t, 2H); 2.5 (t, 2H); 2.1 (t, 2H); 1.3 (t, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([I:14])=[C:10]2[C:6]=1[CH:7](O)[N:8]([C:16]([CH3:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17])[C:9]2=[O:15].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.O>[N+](C)([O-])=O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([I:14])=[C:10]2[C:6]=1[CH2:7][N:8]([C:16]([CH3:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17])[C:9]2=[O:15]
Reactant: COCOc1ccc(I)c2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: C[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: COCOc1ccc(I)c2c1CN(C(C)(C)c1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
In a similar manner to Step 4 of Example 16, 4-methoxymethoxy-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (1.15 g, 2.54 mmol) was dissolved in nitromethane (58 mL), and the solution was added with trifluoroacetic acid (1.20 mL, 7.62 mmol) and triethylsilane (0.587 mL, 7.62 mmol), followed by stirring at room temperature for 30 minutes. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (chloroform/methanol=100/0, 99/1, hexane/ethyl acetate=80/20, 60/40) to obtain 4-methoxymethoxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (935 mg, yield 84%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.CN(C)[CH:21]=[O:22].P(Cl)(Cl)([Cl:26])=O>C(Cl)(Cl)Cl>[Cl:26][C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[C:9]([C:10]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=1)[CH:21]=[O:22]
Reactant: CSc1ccc(CC(=O)c2ccc(F)cc2)cc1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CSc1ccc(C(C=O)=C(Cl)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A 48 g quantity (0.18 mole) of 1-(4-fluorophenyl)-2-(4-methylthiophenyl)-ethanone was suspended in a mixture of 500 ml of chloroform and 57 ml (0.74 mole) of N,N-dimethylformamide. To the suspension was added dropwise 60 ml (0.64 mole) of phosphorus oxychloride with stirring over a period of 30 minutes with cooling in an ice-saline solution bath. After the addition, the resulting mixture was further stirred at 20° C. for 2 hours and refluxed with heating for 18 hours. After being cooled to room temperature, the reaction mixture was added to ice water and then extracted with chloroform. The organic layer was washed with water and a saturated saline solution in this sequence and dried over magnesium sulfate, followed by concentration under reduced pressure. The resulting crystals were washed with a 1:3 mixture of diethyl ether and n-hexane, giving 53 g (94%) of the desired product in the form of a mixture of E- and Z-isomers as light brown solids.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1.Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:14][C:15]([OH:17])=[O:16])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C=O)cc1OC
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1ccc(C=CC(=O)O)cc1OC

Procedure:
3,4-Dimethoxybenzaldehyde (5 g), malonic acid (4.7 g), piperidine (0.5 ml) and pyridine (15 ml) were refluxed for six hours. The reaction mixture was poured into ice-cold water and acidified with 6M hydrochloric acid. The resultant solid was filtered, washed with water and dried under vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH2:22][CH3:23])=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:5][CH:4]=1.[C:31](Cl)(=[O:34])[CH2:32][CH3:33]>>[CH2:22]([N:21]([CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:10]2[S:11][C:7]3[C:6]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:24])=[CH:15][CH:16]=1)[C:31](=[O:34])[CH2:32][CH3:33])[CH3:23]
Reactant: CCC(=O)Cl
Reactant: CCNCc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1
Product: CCC(=O)N(CC)Cc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1

Procedure:
Using N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-ethylaminomethyl-benzamide and propionyl chloride, the title compound was prepared as white solid (47% yield). MS: m/e=483(M+H+).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]([F:17])([F:16])[CH2:14][OH:15].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([O:15][CH2:14][C:13]([F:17])([F:16])[F:12])[CH:7]=1
Reactant: OCC(F)(F)F
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1OCC(F)(F)F
Reaction time: 8 h
Yield: 66.5 %

Procedure:
A mixture of 2,4-difluoro-1-nitrobenzene (10 g, 62.9 mmol) and 2,2,2-trifluoroethanol (6.29 g, 62.9 mmol) in THF (100 mL) at 25° C. was treated with Cs2CO3 (20.5 g, 62.9 mmol) and stirred for 8 hours before being diluted with the addition of water and extracted with EtOAc. The organic extract was dried (Na2SO4), concentrated, and subjected to flash chromatography (3% EtOAc-petroleum ether) to give 4-fluoro-1-nitro-2-[(2,2,2-trifluoroethyl)oxy]benzene (10 g, 67%) as a yellow solid. MS (m/z) 240.0 (M+H+).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18]([OH:20])=O)=[CH:16][N:17]=3)[CH:14]=2)=[CH:5][CH:4]=1.[NH2:23][C:24]1[CH:29]=[C:28]([C:30]([NH:32]O)=[NH:31])[CH:27]=[CH:26][N:25]=1>>[F:22][C:2]([F:21])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18]4[O:20][N:32]=[C:30]([C:28]5[CH:27]=[CH:26][N:25]=[C:24]([NH2:23])[CH:29]=5)[N:31]=4)=[CH:16][N:17]=3)[CH:14]=2)=[CH:7][CH:8]=1
Reactant: N=C(NO)c1ccnc(N)c1
Reactant: O=C(O)c1cnc2ccc(-c3ccc(C(F)(F)F)cc3)cn12
Product: Nc1cc(-c2noc(-c3cnc4ccc(-c5ccc(C(F)(F)F)cc5)cn34)n2)ccn1

Procedure:
The title compound was prepared from 6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.35) (153 mg, 0.5 mmol) and 2-amino-N-hydroxy-pyridine-4-carboxamidine (example B.6) (114 mg, 0.75 mmol) according to general procedure II. Obtained after purification by column chromatography on silica gel (dichloromethane/MeOH 16:1)) and crystallization (MeOH/dichloromethane/hexane) as an off-white solid (80 mg, 38%). MS (EI) 422.9 [(M)+]; mp 280° C.
Reaction SMILES: N[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.N([O-])=O.[Na+].CCOCC.CCCCCC.[ClH:25]>O>[Cl:25][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Nc1ncc(Cl)cc1Cl
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: Clc1cnc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Amino-3,5-dichloropyridine (21.0 g.) is dissolved in conc. HCl (200 ml.), then cooled with ice. To this solution, NaNO2 (48 g.) in water (60 ml.) is added slowly over 30 minutes. The reaction mixture is stirred at 0° for 1 hour and then 50° for 1 hour. The mixture is then poured into ice-water and extracted with ether. The combined extracts are washed, dried and evaporated to dryness to give yellow solid. The solid is stirred with 25% ether/hexane and filtered. The filtrate is concentrated and washed again with 25% ether/hexane to give 2,3,5-trichloropyridine (12 g.).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19](=[S:21])[NH2:20])=[CH:15]2)(=[O:8])=[O:7].N[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1S.Cl.C(O)CO>O>[S:21]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:20]=[C:19]1[C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8]
Reactant: NC(=S)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: Nc1ccccc1S
Agent: Cl
Solvent: OCCO
Solvent: O
Product: O=S(=O)(Nc1cccc2cc(-c3nc4ccccc4s3)[nH]c12)c1cccs1
Temperature: 100 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
A mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.30 g), 2-aminothiophenol (0.10 mL), concentrated hydrochloric acid (0.5 mL) and ethylene glycol (6 mL) was stirred at 100° C. overnight. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (0.14 g, yield 38%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 201-202° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.C([S:39][C:40]([CH3:48])([CH3:47])[C@@H:41]([C:43]([O:45][CH3:46])=[O:44])[NH2:42])C1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([NH:42][C@H:41]([C:43]([O:45][CH3:46])=[O:44])[C:40]([SH:39])([CH3:48])[CH3:47])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](N)C(C)(C)SCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H](NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(C)(C)S
Temperature: -70 °C

Procedure:
146 g of t-butoxycarbonyl proline are dissolved in 1500 ml of methylene chloride. 150 ml of N-methylmorpholine are added to the solution. The solution is cooled to -70° C. 89 ml of isobutylchloroformate are added. The reaction mixture is warmed to -15° C. and then cooled to -70° C. 197 g of methyl S-benzylpenicillaminate hydrochloride are added to the reaction mixture. The reaction mixture is stirred for sixteen hours at room temperature. The reaction mixture is extracted three times with 1.0 M potassium bisulfate and once with brine. The methylene chloride solution is dried over anhydrous sodium sulfate, filtered and stripped of solvent. The residue is dissolved in a minimum of diethyl ether. The ether solution is added to cold rapidly stirring hexane. The white precipitate is filtered and dried to afford the product, methyl t-butoxycarbonylprolylpenicillaminate.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=2)O1.Br[C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[C:34]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:35]=1[CH2:36][CH2:37][N:38]([S:44]([NH:47][C:48]1[S:52][N:51]=[CH:50][N:49]=1)(=[O:46])=[O:45])[CH2:39]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O>[S:52]1[C:48]([NH:47][S:44]([N:38]2[CH2:37][CH2:36][C:35]3[C:40](=[CH:41][CH:42]=[CH:43][C:34]=3[C:25]3[CH:26]=[CH:27][C:28]([C:30]([F:33])([F:32])[F:31])=[CH:29][C:24]=3[C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH:10]=3)[CH2:39]2)(=[O:46])=[O:45])=[N:49][CH:50]=[N:51]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=S(=O)(Nc1ncns1)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2Br)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2-c2cccc3c2CCN(S(=O)(=O)Nc2ncns2)C3)CC1
Yield: 53 %

Procedure:
A solution of Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, Mo., 0.136 g, 0.193 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Frontier Scientific, Logan, Utah, 1.191 g, 3.85 mmol), 5-(2-bromo-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (Example 4, 1.000 g, 1.925 mmol), and potassium phosphate (1.635 g, 7.70 mmol) in 20 mL dioxane, 10 mL water was heated to 120° C. for 2 hours. The reaction mixture was diluted with EtOAc and washed with 1 N citric acid solution. The organics were dried over MgSO4 and concentrated. Purification of the resulting residue by silica gel column chromatography (0 to 100% EtOAc/heptane) gave tert-butyl 4-(2-(2-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.635 g, 1.021 mmol). [M+H]+=522.0 1H NMR (400 MHz, Acetone-d6) δ ppm: 8.28 (s, 1H), 7.63-7.70 (m, 2H), 7.43 (d, J=7.8 Hz, 1H), 7.15-7.30 (m, 2H), 7.07 (d, J=7.4 Hz, 1H), 5.72 (s, 1H), 4.31-4.44 (m, 2H), 3.87 (br. s., 2H), 3.41-3.48 (m, 1H), 3.16-3.36 (m, 1H), 2.78 (br. s., 4H), 2.69 (m, 1H), 2.48-2.55 (m, 1H), 1.37-1.47 (m, 9H)
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][OH:6])[CH2:2][CH3:3].[C:12](O)(=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>O>[C:12]([O:6][CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCC(CO)CCC
Reactant: CCCCCCCC(=O)O
Solvent: O
Product: CCCCCCCC(=O)OCC(CCC)CCCCC
Yield: 99.3 %

Procedure:
158.3 g 2-propylheptanol (1 mol) and 144.2 g caprylic acid (1 mol) were heated for 5 h to 220° C. on a water separator together with 0.30 g Fascat® 2001 (Sn oxalate: 0.1% by weight, based on the composition as a whole). After the separation of water had stopped, the crude product was distilled in an oil pump vacuum through a 250 mm Vigreux column (T=92-94° C.). 282.4 g of a colorless oil were obtained: OHV=<1, AV=<0.1.
Reaction SMILES: [N:1]([CH:4]1[CH2:24][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][C:10]=3F)=[N+:2]=[N-:3].[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([OH:36])([C:34]#[CH:35])[CH3:33])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]([C:34]2[N:1]([C@H:4]3[CH2:24][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[N:2]=[N:3][CH:35]=2)([OH:36])[CH3:33])=[CH:30][CH:31]=1
Reactant: CCCOC(=O)Cc1c2n(c3c(F)cccc13)CC(N=[N+]=[N-])CC2
Reactant: C#CC(C)(O)c1ccc(F)cc1
Product: CC(O)(c1ccc(F)cc1)c1cnnn1[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using procedures described in EXAMPLE 8 from propyl (7-azido-4-fluoro-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate and 2-(4-fluorophenyl)but-3-yn-2-ol. Separation of the resulting diastereoisomers was performed at the ester stage by flash chromatography using a gradient of 10-100% EA/Hex afforded 2 esters. The faster eluting enantiomeric mixture was resolved on chiral HPLC using a 4.6×250 mm Chiralcel OD column eluting with 20% iPrOH, 20% EtOH, 59.75% Hexanes and 0.25% Et3N at 1 mL/min and 254 nm. Retention times=6.9 and 8.4 min. The 2 resulting esters were hydrolyzed separately to afford EXAMPLE 31.1 and 31.2 respectively. The slower eluting enantiomeric mixture was resolved on chiral HPLC using a 4.6×250 mm Chiralcel OD eluting with 20% iPrOH, 20% EtOH, 60% Hexanes at 1 mL/min and 254 nm. Retention times=8.7 and 11.6 min. The 2 resulting esters were hydrolyzed separately to afford EXAMPLE 31.3 and 31.4 respectively. MS (+ESI) m/z: 453.1.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:11]2[CH:12]([NH:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([NH2:26])[CH:22]=4)[N:17]=3)[CH2:13][O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1.Cl[C:28](OC1C=CC([N+]([O-])=O)=CC=1)=[O:29].Cl.Cl.[CH:42]([N:45]1[CH2:50][CH2:49][CH:48]([NH2:51])[CH2:47][CH2:46]1)([CH3:44])[CH3:43]>>[CH:42]([N:45]1[CH2:50][CH2:49][CH:48]([NH:51][C:28]([NH:26][C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]([NH:15][CH:12]2[C:11]4[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][CH:8]=[CH:9][C:10]=4[O:14][CH2:13]2)[CH:25]=[CH:24]3)=[O:29])[CH2:47][CH2:46]1)([CH3:44])[CH3:43]
Reactant: CC(C)N1CCC(N)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COCCOc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CO2
Agent: Cl
Product: COCCOc1cccc2c1C(Nc1ccc3cc(NC(=O)NC4CCN(C(C)C)CC4)ccc3n1)CO2

Procedure:
The title compound was prepared from rac-N2-[4-(2-methoxy-ethoxy)-2,3-dihydro-benzofuran-3-yl]-quinoline-2,6-diamine (Example 174) (200 mg, 0.57 mmol), 4-nitrophenyl chloroformate (115 mg, 0.57 mmol) and 1-isopropyl-piperidin-4-ylamine dihydrochloride (CAS no: 534596-29-7) (122 mg, 0.57 mmol) in accordance with the general method 4 described in example 170 step C and was obtained as an off-white solid (210 mg, 71%); MS: m/e=520.5 (M+H+).