Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[CH:15]=2)[CH:10]=[N:9][CH:8]=1)(=O)=O.[CH:28]([C:30]1[CH:35]=[CH:34][C:33](OB(O)O)=[CH:32][CH:31]=1)=[O:29]>>[CH:28]([C:30]1[CH:35]=[CH:34][C:33]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[CH:15]=3)[CH:10]=[N:9][CH:8]=2)=[CH:32][CH:31]=1)=[O:29]
Reactant: O=Cc1ccc(OB(O)O)cc1
Reactant: C[Si](C)(C)CCOC(=O)c1ccc2cncc(OS(=O)(=O)C(F)(F)F)c2c1
Product: C[Si](C)(C)CCOC(=O)c1ccc2cncc(-c3ccc(C=O)cc3)c2c1
Yield: 79.7 %

Procedure:
Using 2-(trimethylsilyl)ethyl 4-{[(trifluoromethyl)sulfonyl]oxy}isoquinoline-6-carboxylate (600 mg, 1.42 mmol) and 4-formylphenylboric acid (320 mg, 2.14 mmol), the desired title compound (427 mg, yield 79%) was obtained by the same method as in Example 8 (8a).
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C.[CH2:30]([O:37][C:38]([N:40]1[CH2:47][C@@H:46]([OH:48])[CH2:45][C@H:41]1[C:42](O)=[O:43])=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O>[CH2:30]([O:37][C:38]([N:40]1[CH2:47][C@@H:46]([OH:48])[CH2:45][C@H:41]1[C:42]([NH:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:43])=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)[C@@H]1C[C@H](O)CN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)N
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](O)CN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 24.7 %

Procedure:
4.56 g (16.58 mmol) of diphenylphosphoryl azide, 1.50 g (20.55 mmol) of t-butylamine and 2.78 g (27.80 mmol) of triethylamine were successively added, whilst ice-cooling, to a solution of 3.68 g (13.90 mmol) of (4S)-1-benzyloxycarbonyl-4-hydroxy-L-proline in 30 ml of dimethylformamide, and the mixture was stirred for 5 hours. At the end of this time, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic extract was washed with a 10% w/v aqueous solution of citric acid, with a 10% w/v aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which the resulting mixture was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was recrystallized from a mixture of methylene chloride and diethyl ether, to give 1.10 g of the title compound as colorless crystals, melting at 129°-130° C.
Reaction SMILES: I[CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([S:13][CH3:14])[CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:15].[NH3:16]>C(Cl)(Cl)Cl>[NH2:16][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([S:13][CH3:14])[CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:15]
Reactant: CSc1ccc2c(c1)CCC(I)C(=O)N2
Reactant: N
Solvent: ClC(Cl)Cl
Product: CSc1ccc2c(c1)CCC(N)C(=O)N2
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 0.5 g of 3-iodo-7-methylthio-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one and 15 g of ammonia in 20 mL of chloroform was shaken in a bomb at 100° C. for 3 hours. The bomb was cooled, vented and the contents transferred to a separatory funnel. The mixture was washed with water, dried over magnesium sulfate, filtered and solvents removed under vacuum to give the product. 1H NMR (200 MHz,CDCl3): 1.90 (m,1H), 2.3-2.7 (m,2H), 2.45 (s,3H), 2.85 (m,1H), 3.39 (dd;8,11Hz;1H), 6.89 (d,8Hz,1H), 7.10 (m,2H), 8.3 (br s,1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:6]2[S:11][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:9][C:7]=2[N:8]=1.C(N(CC)CC)C.[CH2:32]([S:34](Cl)(=[O:36])=[O:35])[CH3:33]>C(Cl)Cl>[Cl:2][C:3]1[N:4]=[C:5]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[C:6]2[S:11][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([S:34]([CH2:32][CH3:33])(=[O:36])=[O:35])[CH2:15][CH2:14]3)=[CH:9][C:7]=2[N:8]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCNCC3)cc2n1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C

Procedure:
To 2-Chloro-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine HCl salt from General Procedure B-3 (50 mg) in dry DCM (3 ml) and triethylamine (3.5 equiv., 60 ul) was added ethanesulfonyl chloride (1.1 equiv., 10 ul) at 0° C. and the reaction mixture was allowed to warm up to room temperature overnight. Extraction with DCM/brine gave 2-chloro-6-(4-ethanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine as a crude product (67 mg), which was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica and ether trituration gave 291. NMR (CDCl3): 1.40 (3H, t, J=7.4), 2.65-2.69 (4H, m), 3.00 (2H, q, J=7.4), 3.37-3.41 (4H, m), 3.86 (2H, s), 3.89-3.91 (4H, m), 4.03-4.05 (4H, m), 5.23 (2H, br), 9.35 (2H, s). MS (ESI+): MH+505.15 (100%)
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl.[CH:5]1([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][C:16]([S:18]([C:21]([CH3:26])([CH3:25])[C:22](Cl)=[O:23])(=[O:20])=[O:19])=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:7][CH2:6]1>ClCCl>[CH:5]1([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][C:16]([S:18]([C:21]([CH3:26])([CH3:25])[C:22]([N:2]([CH3:3])[CH3:1])=[O:23])(=[O:20])=[O:19])=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:7][CH2:6]1
Reactant: CNC
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)C(=O)Cl)ccc2n1CC1CC1
Agent: Cl
Solvent: ClCCl
Product: CN(C)C(=O)C(C)(C)S(=O)(=O)c1ccc2c(c1)nc(CC(C)(C)C)n2CC1CC1
Reaction time: 1.5 h
Yield: 47 %

Procedure:
To a solution of dimethylamine (2 mol/L tetrahydrofurane solution, 0.950 mL, 1.90 mmol) in dichloromethane (3 mL) was added 2-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}-2-methylpropanoyl chloride hydrochloride (Step A, 175 mg, 0.380 mmol) in dichloromethane (2 mL) at room temperature. After stirring at the same temperature for 1.5 h, the mixture was diluted with dichloromethane. The whole was washed with saturated sodium hydrogencarbonate aqueous solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by HPLC (ODS, gradient elution with acetonitrile/0.01% aq. NH3=4:96 to 96:4, by volume; flow rate 40 mL/min) to afford the title compound (75 mg, 47%) as an amorphous.
Reaction SMILES: Cl[C:2]1([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9](=[O:16])[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>C(#N)C>[N:24]1([C:2]2([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9](=[O:16])[C:8]3[C:3]2=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: c1c[nH]cn1
Reactant: Cc1ccc(C2(Cl)c3ccccc3C(=O)c3ccccc32)cc1
Solvent: CC#N
Product: Cc1ccc(C2(n3ccnc3)c3ccccc3C(=O)c3ccccc32)cc1
Yield: 41.7 %

Procedure:
36.2 g (0.113 mol) of 9-chloro-9,10-dihydro-9-(4-methylphenyl)-10-oxo-anthracene and 20.4 g (0.3 mol) of imidazole in 400 ml of absolute acetonitrile are heated under reflux for 5 hours. Thereafter, the solvent is distilled off in vacuo and the residue is taken up in 500 ml of methylene chloride. The methylene chloride solution is washed twice with 1,000 ml of water each time and the organic phase is separated off, dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. The yellow, oily residue is recrystallised from 300 ml of acetonitrile. 16.5 g (40.6% of theory) of 9,10-dihydro-9-imidazol-1-yl-9-(4-methylphenyl)-10-oxo-anthracene of melting point 200°-204° C. are obtained.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[C:14]([I:15])[C:9]=2[O:8][CH2:7][C:6]1=O)[CH2:2][CH2:3][CH3:4].B1C2CCCC1CCC2.C(CN)O>O1CCCC1>[CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[C:14]([I:15])[C:9]=2[O:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)COc2c(I)cc(C(=O)OC)cc21
Agent: B1C2CCCC1CCC2
Solvent: NCCO
Solvent: C1CCOC1
Product: CCCCN1CCOc2c(I)cc(C(=O)OC)cc21
Temperature: 25 °C
Yield: 91.5 %

Procedure:
A solution of Methyl 4-butyl-8-iodo-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (680 mg) and 9-BBN (900 mg) in tetrahydrofuran (30 mL) was heated at reflux for 1.5 h. The mixture was cooled to room temperature, ethanolamine (0.22 mL) was added, and the resulting solution was concentrated under reduced pressure. The residue was washed with hexanes, filtered, and the filtrate was concentrated under reduced pressure. Purification by flash column chromatography (silica, 10% ethyl acetate/hexanes) afforded 600 mg of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.75, 7.28, 4.34, 3.86, 3.36, 3.28, 1.58, 1.40, 0.96.
Reaction SMILES: [CH3:1][N:2]([CH2:19][CH2:20][CH3:21])[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]2[O:15][CH:16]=[CH:17][N:18]=2)[CH:13]=1)[C:8]([OH:10])=O)=[O:4].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:57][C@@H:58]([CH2:72][C:73]1[CH:78]=[C:77]([F:79])[CH:76]=[C:75]([F:80])[CH:74]=1)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=1>CN(C=O)C>[F:79][C:77]1[CH:78]=[C:73]([CH:74]=[C:75]([F:80])[CH:76]=1)[CH2:72][C@H:58]([NH:57][C:8](=[O:10])[C:7]1[CH:11]=[C:12]([C:14]2[O:15][CH:16]=[CH:17][N:18]=2)[CH:13]=[C:5]([C:3]([N:2]([CH3:1])[CH2:19][CH2:20][CH3:21])=[O:4])[CH:6]=1)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCN(C)C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCN(C)C(=O)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)cc(-c2ncco2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-{[Methyl(propyl)amino]carbonyl}-5-(1,3-oxazol-2-yl)benzoic acid (350 mg, 1.2 mmol) in DMF (5 mL) is added diisopropylethylamine (835 μL, 4.8 mmol), HATU (554 mg, 1.5 mmol), then (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride prepared by the method of Example SP-272 (488 mg, 1.2 mmol). The reaction is stirred for 16 h at room temperature. The reaction is partitioned between chloroform and water. The organic layer is washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 9% methanol/chloroform) gives the title compound. ESI MS m/z 605.3 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](O)=[O:14])=[O:8]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([Cl:3])=[O:14])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(CCl)Nc1cccc(C(=O)O)c1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(CCl)Nc1cccc(C(=O)Cl)c1
Yield: 80 %

Procedure:
To a warm (55°-60° C.) solution of 250 ml. of thionyl chloride and 50 ml. of chloroform and 6 drops of pyridine is added 3-(chloroacetylamino)benzoic acid (150 g., 0.702 mole) in 3 equal portions at 0.5 hr. intervals. After the addition is complete, the reaction mixture is warmed to a temperature of 55°-65° C. for 2 hrs., cooled and diluted with 500 ml. of petroleum ether (b.p. 30°-60° C.). The precipitate which forms is collected, washed with petroleum ether (b.p. 30°-60° C.) and dried under vacuum over potassium hydroxide at room temperature to afford 143 g. (80% yield) of 3-(chloroacetylamino)benzoyl chloride, m.p. 106°-108° C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12][C:11]3=O)=[O:7])=[CH:4][CH:3]=1.P(Br)(Br)[Br:22].C([O-])(O)=O.[Na+]>CN(C=O)C.O>[Br:22][C:11]1[C:10]2[C:15](=[CH:16][CH:17]=[C:8]([C:6]([C:5]3[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:7])[CH:9]=2)[N:14]=[CH:13][CH:12]=1
Reactant: BrP(Br)Br
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2[nH]ccc(=O)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cl)cc1)c1ccc2nccc(Br)c2c1
Reaction time: 0.5 h

Procedure:
To a suspension of 6-(4-chlorobenzoyl)quinolin-4(1H)-one (1.26 g, 4.45 mmol) in DMF (8 mL) at room temperature was added slowly phosphorous tribromide. The resulting mixture was stirred under argon for 30 min. The reaction mixture was made basic by the addition of solid NaHCO3 until pH was greater than 10, diluted with water and filtered. The product was washed with several portion of water and dried to yield (4-bromoquinolin-6-yl)(4-chlorophenyl)methanone. (M+H)+: 346, 348.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[CH2:4][O:5]/[N:6]=[C:7](/[C:13](=[O:15])[CH3:14])\[C:8]([O:10][CH2:11][CH3:12])=[O:9].[Br:21]Br>>[Br:21][CH2:14][C:13](=[O:15])/[C:7](=[N:6]/[O:5][CH2:4][C:3]1[C:2]([Cl:1])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:20])/[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: BrBr
Reactant: CCOC(=O)/C(=N\OCc1c(Cl)cccc1Cl)C(C)=O
Product: CCOC(=O)/C(=N\OCc1c(Cl)cccc1Cl)C(=O)CBr

Procedure:
Ethyl (Z)-2-(2,6-dichlorobenzyloxyimino)-3-oxobutyrate (5.8 g) was reacted with bromine (0.94 ml) as described in Example 4c to give the title compound (7.2 g), δH (CDCl3) 1.31 (3H, t), 4.35 (2H, s), 4.45 (2H, q), 5.73 (2H, s), and 7.43 (3H, m).
Reaction SMILES: [N+:1]([O:4][CH2:5][C:6]([CH2:16][O:17][N+:18]([O-:20])=[O:19])([CH2:11][O:12][N+:13]([O-:15])=[O:14])[C:7](OC)=[O:8])([O-:3])=[O:2].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>C(Cl)(Cl)Cl>[CH2:21]([NH:28][C:7](=[O:8])[C:6]([CH2:16][O:17][N+:18]([O-:20])=[O:19])([CH2:11][O:12][N+:13]([O-:15])=[O:14])[CH2:5][O:4][N+:1]([O-:3])=[O:2])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)C(CO[N+](=O)[O-])(CO[N+](=O)[O-])CO[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccccc1)C(CO[N+](=O)[O-])(CO[N+](=O)[O-])CO[N+](=O)[O-]
Yield: 73 %

Procedure:
1 g (3.5 mmol) of methyl 3-nitryloxy-2,2-bis(nitryloxymethyl)propionate is heated with 3 ml of benzylamine and 100 ml of ammonium chloride for 3 hours at 130° C., cooled, taken up in 50 ml of chloroform and washed in sequence with water, dilute hydrochloric acid, aqueous bicarbonate solution and again with water. The crude product obtained after evaporating off the solvent is purified column chromatographically. 3-nitryloxy-2,2-bis(nitryloxymethyl)propionic acid N-benzylamide is obtained as a colourless oil. Yield: 73%.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 8 h

Procedure:
1.7 g (10.2 mmol) of ethyl 4-hydroxybenzoate, 1.76 g (9.3 mmol) of 1-t-butoxycarbonyl-4-hydroxypiperidine and 2.44 g (9.3 mmol) of triphenylphosphine were dissolved in 40 ml of tetrahydrofuran. 1.62 g (9.3 mmol) of diethyl azodicarboxylate was added to the solution at room temperature, and they were stirred overnight. The crude product was obtained by the same isolation process as that of step 1 in Example 1 with ethyl acetate as the extractant. After the purification by the silica gel column chromatography, the title compound was obtained.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Cl.[Cl:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH2:14])=[CH:9][CH:8]=1.C(N(CC)CC)C.[Br-].[K+]>CN1CCCC1=O>[Cl:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH:14][CH2:3][CH:2]([F:5])[F:1])=[CH:9][CH:8]=1
Reactant: FC(F)CCl
Reactant: NCc1ccc(Cl)nc1
Agent: [Br-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: FC(F)CNCc1ccc(Cl)nc1
Temperature: 120 °C
Yield: 70.8 %

Procedure:
13.7 g (0.135 mol) of 2,2-difluoro-1-chloroethane, 10 g (0.067 mol) of 1-(6-chloropyridin-3-yl)methanamine and 8.2 g of triethylamine are initially charged with 31 g of N-methylpyrrolidone. In addition, 4 g (0.033 mol) of potassium bromide are added. The mixture is heated to 120° C. under autogenous pressure in an autoclave for 16 hours and then cooled again to 80° C. The N-methylpyrrolidone is distilled off at 80° C. under reduced pressure and the reaction mixture is poured onto 20 ml of 32% hydrochloric acid. The mixture is concentrated to dryness under reduced pressure and then adjusted to pH 12 with 10 ml of 45% NaOH. The mixture is extracted three times with 30 ml of toluene and the organic phases are distilled under reduced pressure. This gives 9.8 g of N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethanamine (corresponds to 71% yield).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[C:14]3[CH:13]=[CH:12][C:11]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:10][C:9]=3[NH:8][N:7]=2)=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35].O>CN(C)C=O>[CH:1]1([C:4]([C:6]2[C:14]3[CH:13]=[CH:12][C:11]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:10][C:9]=3[N:8]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[N:7]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C(c1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(C(=O)C2CC2)c2c1CC(c1ccccc1)(c1ccccc1)C=C2
Temperature: 20 °C
Yield: 70.9 %

Procedure:
A solution of 2.55 g of cyclopropyl(6,6-diphenyl-6,7-dihydro-1H-indazol-3-yl)methanone in 40 cm3 of dimethylformamide is added dropwise at a temperature in the region of 5° C. to a suspension, cooled to this same temperature, of 0.39 g of sodium hydride (at 60% in oil) in 20 cm3 of dimethylformamide. After stirring the mixture at this same temperature for about one and a half hours, a solution of 1.87 g of (2-chloromethoxyethyl)trimethylsilane in 20 cm3 of dimethylformamide is added dropwise without exceeding a temperature of 10° C. After warming to a temperature in the region of 20° C., the mixture is stirred for 2 hours at this same temperature. 20 cm3 of water are then added and the mixture is concentrated under reduced pressure (13 kPa). The residue is taken up in 80 cm3 of water and extracted three times with 60 cm3 of dichloromethane. The combined organic phases are dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. After flash chromatography on a column of silica [eluent: dichloromethane/methanol (99/1 by volume)], 2.5 g of cyclopropyl(6,6-diphenyl-1-(2-trimethylsilanylethoxymethyl)-6,7-dihydro-1H-indazol-3-yl)methanone are thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]([C@@H:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][N:13]1[C:22](=[O:41])[C@@H:23]([NH:27][C:28](=[O:40])[C@@H:29]([N:31](C)[C:32](=O)OC(C)(C)C)[CH3:30])[CH:24]([CH3:26])[CH3:25])=[O:11].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]([C@@H:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][N:13]1[C:22](=[O:41])[C@@H:23]([NH:27][C:28](=[O:40])[C@@H:29]([NH:31][CH3:32])[CH3:30])[CH:24]([CH3:26])[CH3:25])=[O:11]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1Cc2ccccc2C[C@H]1C(=O)Nc1c(F)cccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1Cc2ccccc2C[C@H]1C(=O)Nc1c(F)cccc1F)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (S)-1-((S)-1-((S)-3-(2,6-difluorophenylcarbamoyl)-3,4-dihydro isoquinolin-2 (1H)-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate (138 mg, 241 μmol, Eq: 1.00) in DCM (2 mL) was added TFA (2.96 g, 2 mL, 26.0 mmol, Eq: 108) and the resulting solution stirred at RT for 1 h. The mixture was concentrated in vacuo, saturated NaHCO3 was added to the residue and the resulting mixture extracted with DCM. The combined extracts were dried over Na2SO4 and concentrated in vacuo. The residue was treated with ether/hexanes to give (S)-2-[(S)-3-methyl-2-((S)-2-methylamino-propionylamino)-butyryl]-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (2,6-difluoro-phenyl)-amide as a white solid which was used without purification (70 mg), m/z=473 (M+H).
Reaction SMILES: O([C:8]([NH:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:9])C1C=CC=CC=1.Cl.[NH2:18][N:19]1[CH2:24][CH:23]=[CH:22][CH2:21][CH2:20]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N:14]1[CH:13]=[CH:12][C:11]([NH:10][C:8]([NH:18][N:19]2[CH2:20][CH:21]=[CH:22][CH2:23][CH2:24]2)=[O:9])=[CH:16][CH:15]=1
Reactant: NN1CC=CCC1
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccncc1)NN1CC=CCC1
Yield: 45.9 %

Procedure:
A solution of 4-(phenoxycarbonylamino)pyridine (4.284 g), N-amino-1,2,3,6-tetrahydropyridine hydrochloride (4.038 g) and triethylamine (3.036 g) in chloroform (70 ml) was refluxed for 20 hours. After evaporation of chloroform, the residue was extracted with ethyl acetate (200 ml). The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (52 g) using chloroform to give N-[(4-pyridylcarbamoyl)amino]-1,2,3,6-tetrahydropyridine (2.005 g).
Reaction SMILES: Cl.Cl[C:3]1[S:7][C:6]([C:8](=[O:14])[CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16].[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[SH:26].C(=O)([O-])[O-].[K+].[K+].Cl>>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[S:26][C:3]1[S:7][C:6]([C:8](=[O:14])[CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16]
Reactant: CN(C)CCC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: Sc1ccc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(C)CCC(=O)c1cc([N+](=O)[O-])c(Sc2ccc(Cl)cc2Cl)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 17 %

Procedure:
To a solution of 1-(5-chloro-4-nitro-2-thienyl)-3-dimethylamino-propan-1-one hydrochloride salt from the above (0.180 g, 0.687 mmol) and 2,4-dichlorobenzenethiol (0.123 g, 0.687 mmol) in N,N-dimethylformide (3 mL), was added potassium carbonate (0.237 g, 1.71 mmol). The resulting reaction mixture was stirred at ambient temperature for 5 hours. After this time, the reaction mixture was quenched with ice water and stirred at room temperature for 20 min and the precipitate which formed was collected by filtration and washed with water, and dried under vacuum. The crude solid was purified by silica gel chromatography to afford a yellow solid. The resulting solid was treated with hydrochloric acid (2 M). The solution was concentrated and dried under vacuum to afford the corresponding hydrochloride salt of the title product (90 mg, 17% yield). 1H NMR (400 MHz, MeOD) δ: 8.61 (1H, s), 8.05 (1H, m), 7.98 (1H, dd), 7.72 (1H, dd), 3.48 (2H, m), 3.33 (2H, m), 2.78 (3H, s). MS m/z: 404.9 [M+H]+.