Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][CH2:12][NH:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C12CNCC1CCN2[C:24]([O:26][CH2:27][CH3:28])=[O:25].ClC(OCC)=O>>[CH2:1]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][CH2:12][N:13]2[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CC3CCNC3C2)cc1
Reactant: CCOC(=O)N1CCC2CNCC21
Agent: CCOC(=O)Cl
Product: CCOC(=O)N1CCC2CN(Cc3ccccc3)CC21

Procedure:
Ethyl 2,7-diazabicyclo[3.3.0]octane-2-carboxylate 7-Benzyl-2,7-diazabicyclo[3.3.0]octane (Example Jc) is reacted with ethyl chloroformate analogously to Example Oa) to give ethyl 7-benzyl-2,7-diazabicyclo[3.3.0]octane-2-carboxylate, and this is then debenzylated hydrogenolyrically analogously to Example Jd). A colorless oil of boiling point 90° C./0.1 mbar is obtained.
Reaction SMILES: [CH2:1]([O:11][C:12]([CH:14]([C:20]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[O:21])[N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9].[Cl:33]Cl>C(Cl)(Cl)(Cl)Cl.P(Cl)(Cl)Cl>[CH2:23]([O:22][C:20]([C:14]([C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])=[O:13])([Cl:33])[N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)=[O:21])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)CCCCCCCOC(=O)C(C(=O)OCCCCCCCC(C)C)n1cncn1
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClP(Cl)Cl
Product: CC(C)CCCCCCCOC(=O)C(Cl)(C(=O)OCCCCCCCC(C)C)n1cncn1

Procedure:
1-[bis(isodecyloxycarbonyl)methyl]-1,2,4-triazole, which is the product of Example 12 (15.6g), was dissolved in carbon tetrachloride (20 ml). Phosphorus trichloride (3 drops) was added and the solution was stirred and heated at 60° whilst a slow stream of chlorine was bubbled through it for 1 hour. The solution was then cooled, washed with aqueous sodium sulphite solution and with water, and the solvent was distilled under reduced pressure yielding 1-[bis(isodecyloxycarbonyl)chloromethyl]-1,2,4-triazole (12.9 g), which had a purity of 82.4% as measured by non-aqueous titration with perchloric acid. This compound was evaluated as an extractant for copper by the procedure of Example 1 and the results are presented in Table 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([NH2:21])[CH3:20])=[CH:15][CH:14]=3)=[CH:11][N:12]=2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.Cl[C:34]([O:36][CH3:37])=[O:35]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([NH:21][C:34](=[O:35])[O:36][CH3:37])[CH3:20])=[CH:15][CH:14]=3)=[CH:11][N:12]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)Cl
Reactant: COc1ccc(Oc2ncc(-c3ccc(C(C)N)cc3)s2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NC(C)c1ccc(-c2cnc(Oc3ccc(OC)cc3)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of Example 11D ((110 mg, 0.337 mmol) and diisopropylethylamine (0.5 mL) in methylene chloride (1 mL) cooled to 0° C. was added methyl chloroformate (67 μL, 0.76 mmol, 2.3 eq.). The mixture was stirred at room temperature overnight. The reaction mixture was purified directly on silica gel eluting with an ethyl acetate/hexane gradient (0-30%) to give the title compound (112 mg, 86%). 1H NMR (300 MHz, CDCl3) δ ppm 7.35-7.45 (m, 3 H), 7.27-7.33 (m, 2 H), 7.21-7.26 (m, 2 H), 6.91-7.01 (m, 2 H), 4.73-498 (m, 1 H), 3.83 (s, 3 H), 3.66 (s, 3 H); 1.47 (d, J=6.62 Hz, 3 H) MS (DCI): m/e 385 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[S:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1.[H-].[Na+].O>CS(C)=O>[C:20]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:22][CH:23]=[C:18]([CH2:17][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH:9]3[S:13][C:12](=[O:14])[NH:11][C:10]3=[O:15])=[CH:6][CH:7]=2)[CH:19]=1
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Reactant: ClCc1cccc(-c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1NC(=O)C(Cc2ccc(OCc3cccc(-c4ccccc4)c3)cc2)S1
Temperature: 50 °C
Reaction time: 1 h
Yield: 256.8 %

Procedure:
To a solution of 5-[(4-hydroxyphenyl)methyl]-2,4-thiazolidinedione (0.30 g, 1.3 mmol) in dimethyl sulfoxide (20 mL) were added 3-(chloromethyl)biphenyl (0.26 g, 1.3 mmol) and 60% sodium hydride (0.11 g, 2.6 mmol), and the mixture was stirred at room temperature for 1 hr and further at 50° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=8:2) to give the title compound (1.3 g, yield 96%).
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]([CH2:15]Br)[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=O)C.C1N2CN3CN(C2)C[N:18]1C3.C(Cl)(Cl)[Cl:28]>>[ClH:28].[NH2:18][CH2:15][C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([OH:4])[CH:14]=1
Reactant: COC(=O)c1ccc(CBr)cc1OC(C)=O
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: ClC(Cl)Cl
Product: COC(=O)c1ccc(CN)cc1O
Product: Cl
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of methyl 2-acetoxy-4-bromomethylbenzoate (Regnier G, Canevari R, Le Douarec J-C, Bull. Soc. Chim. Fr. 1966:2821) (10.7 g) and hexamethylenetetramine (17.1 g) in CHCl3 (150 mL) was refluxed for 5 hours, then the solvent was removed (method of Meindl W, v Angerer E, Ruckdeschel G, Schonenberger H, Arch. Pharm. (Weinheim) 1982;315:941). The residue was stirred with MeOH (60 mL) and concentrated HCl (30 mL) at 20° C. for 10 minutes, then the solvent removed. Treatment of the solid residue twice more with HCl/MeOH and evaporation gave a solid, which was washed with CH2Cl2, then treated with saturated KHCO3 solution. The base was extracted with EtOAc and CH2Cl2, then the solvents removed. The crude hydrochloride salt (5.30 g, 70% pure) was precipitated from an ethereal solution of the base upon the addition of HCl gas. A subsample of the above crude base was purified by chromatography on silica gel, eluting with EtOAc/light petroleum (1:2). Acidification of a solution of the purified base gave pure methyl 4-(aminomethyl)-2-hydroxybenzoate hydrochloride; mp (CH2Cl2 /light petroleum) 225°-227° C.
Reaction SMILES: C(Cl)(=O)C1C=CC=CC=1.[S-:10][C:11]#[N:12].[NH4+].[CH2:14]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])[CH2:15][CH3:16]>CC(C)=O.ClCCl>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[N:17]([CH2:14][CH2:15][CH3:16])[C:11]([NH2:12])=[S:10]
Reactant: CCCNc1ccc(Cl)cc1Cl
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: CCCN(C(N)=S)c1ccc(Cl)cc1Cl
Reaction time: 0.25 h
Yield: 82 %

Procedure:
5.1 ml of benzoyl chloride are added under argon and at 0° C. to 3.4 g of ammonium thiocyanate in 80 ml of anhydrous acetone and the reaction mixture is stirred for 15 minutes. 7.48 g of N-propyl-2,4-dichloroaniline (Compound 5-1) in 60 ml of anhydrous acetone are added and the reaction mixture is stirred for 2 hours at room temperature. It is evaporated to dryness, the residue obtained is taken up in dichloromethane, washed with water and dried. 13.5 g of the expected product are obtained in the form of an oil; yield=82%.
Reaction SMILES: [CH:1]([N:4]([S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[OH:15])([CH3:3])[CH3:2].O[CH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[CH:33]=[C:32]([C:37]([O:39]CC)=[O:38])[CH:31]=[CH:30]2>>[CH:1]([N:4]([S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:14])[F:13])=[CH:7][C:6]=1[O:15][CH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[CH:33]=[C:32]([C:37]([OH:39])=[O:38])[CH:31]=[CH:30]2)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc2cc(CO)ccc2c1
Reactant: CC(C)N(c1ccc(C(F)(F)F)cc1O)S(=O)(=O)c1ccccc1
Product: CC(C)N(c1ccc(C(F)(F)F)cc1OCc1ccc2cc(C(=O)O)ccc2c1)S(=O)(=O)c1ccccc1

Procedure:
By using 2-(N-isopropyl-phenylsulfonylamino)-5-trifluoromethylphenol (prepared in Reference Example 24.) and ethyl 6-hydroxymethyl-2-naphthate, the title compound having the following physical data was obtained by the same procedure as Reference Example 18 (b)→Example 2.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:12])=[CH:10][S:11][C:5]2=[N:4][C:3]=1[C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14].[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:24]1[CH:29]=[C:28]([C:2]2[C:7](=[O:8])[N:6]3[C:9]([CH3:12])=[CH:10][S:11][C:5]3=[N:4][C:3]=2[C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1csc2nc([C@H](C)NC(=O)OC(C)(C)C)c(Br)c(=O)n12
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1csc2nc([C@H](C)NC(=O)OC(C)(C)C)c(-c3cccc(F)c3)c(=O)n12
Temperature: 100 °C
Yield: 76.6 %

Procedure:
(S)-tert-Butyl 1-(6-bromo-3-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)ethylcarbamate (5.46 g, 14.1 mmol) and (3-fluorophenyl)boronic acid (2.95 g, 21.1 mmol) were suspected in 1,4-dioxane (110 mL). A solution of sodium carbonate (4.47 g, 42.2 mmol) in water (27 mL) was added to the mixture followed by tetrakis(triphenylphosphine)palladium(0) catalyst (0.81 g, 0.70 mmol). The reaction mixture was degassed and heated under nitrogen at 100° C. for 16 h. HPLC indicated the starting material was consumed. The reaction mixture was cooled to room temperature and water (100 mL) was added. The resultant mixture was extracted with ethyl acetate (2×100 mL). The ethyl acetate solution was washed with saturated aqueous sodium bicarbonate (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography on silica gel using 1-50% ethyl acetate in hexane as eluent to give (S)-tert-butyl 1-(6-(3-fluorophenyl)-3-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)ethylcarbamate (4.34 g, 10.8 mmol, 76%) as an off-white solid. LCMS calculated for C20H23FN3O3S (M+H)+: m/z 404.1. Found 404.1. 1H NMR (500 MHz, DMSO-d6) δ 7.48 (ddd, J=8.1, 7.8, 6.2 Hz, 1H), 7.18 (m, 3H), 7.05 (q, J=1.3 Hz, 1H), 6.96 (d, J=7.5 Hz, 1H), 4.41 (m, 1H), 2.66 (d, J=1.3 Hz, 3H), 1.33 (s, 9H), 1.13 (d, J=6.8 Hz, 3H).
Reaction SMILES: [F-].C([N+](C[CH2:16][CH2:17][CH3:18])(CCCC)CCCC)CCC.C(OC1(O[Si](C)(C)C)CC1)C.C1(P(=[CH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(=O)C1C=CC=CC=1>C1COCC1.C(OCC)C>[C:16]1(=[CH:49][C:50]([O:52][C:53]([CH3:54])([CH3:55])[CH3:56])=[O:51])[CH2:17][CH2:18]1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC1(O[Si](C)(C)C)CC1
Agent: O=C(O)c1ccccc1
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C=C1CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
At room temperature, 55 ml (55 mmol) of a 1 M solution of tetra-n-butylammonium fluoride in THF were added dropwise to a solution of 9.65 g (55.34 mmol) of [(1-ethoxycyclopropyl)oxy](trimethyl)silane, 25 g (66.41 mmol) of tert-butyl (triphenyl-λ5-phosphanylidene)-acetate and 8.11 g (66.41 mmol) of benzoic acid in 240 ml of THF. After 1 h of stirring, the reaction mixture was heated to 80° C. and stirred at this temperature for 2 h. Using a rotary evaporator, the solvent was then distilled off (200 mbar, bath temperature 40° C.). The residue obtained was taken up in diethyl ether and the mixture was cooled to 4° C. and allowed to stand at this temperature for 1 h. The resulting precipitate (triphenylphosphane oxide) was filtered off. Using a rotary evaporator, the filtrate was then freed from the solvent. The crude product obtained was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave 3.58 g (42% of theory) of the title compound.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=3)=[C:13](C(OCC)=O)[C:12]2=[O:32])=[CH:2]1>CN(C)C=O>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[C:12](=[O:32])[CH:13]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=3)[O:15]2)=[CH:2]1
Reactant: CCOC(=O)C1=C(Nc2ccc(OC)c(OC)c2)OC(=Cc2c[nH]c3ncccc23)C1=O
Solvent: CN(C)C=O
Product: COc1ccc(NC2=CC(=O)C(=Cc3c[nH]c4ncccc34)O2)cc1OC
Temperature: 25 °C
Yield: 13.9 %

Procedure:
A solution of the compound (0.043 g, 0.099 mmol) of Example 28 in N,N-dimethylformamide (1.2 mL) was refluxed for 6 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound (0.0050 g, y. 12%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[OH:4].C(N(CC)CC)C.[C:26](Cl)(=[O:29])[CH2:27][CH3:28]>ClCCl>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH2:2][NH:1][C:26](=[O:29])[CH2:27][CH3:28])=[CH:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCC(O)c1ccc(OCc2ccccc2)cc1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NCC(O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 112.2 %

Procedure:
The amine from example 24 (24.8 g, 0.10 mol) was dissolved in dichloromethane (700 ml) and to this was added triethylamine (20.86 ml, 0.115 mol). The reaction mixture was stirred and cooled to 0° C., before propionyl chloride (7.12 ml, 0.082 mol) was added dropwise. The reaction mixture was then allowed to warm to room temperature over 16 hours before quenching with 3M HCl (aq) (20 ml) and water (100 ml). The reaction mixture was then extracted with dichloromethane (3×200 ml) and the combined organic layers dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a clear viscous gum (27.5 g, 0.092 mol, 90%). 1H NMR (CDCl3, 400 MHz) δ: 1.10 (t 3H), 2.19 (q, 2H), 3.32-3.43 (m, 4H), 4.81 (s, 2H), 5.11 (m, 1H), 6.99 (4, 2H), 7.25-7.42 (m, 7H). LRMS: m/z 298 (M-H−).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[C:24]([CH3:32])[CH:23]=3)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:8][O:7][CH2:6]1)=[O:4].[C:33](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH:9]([N:10]([CH3:33])[S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[C:24]([CH3:32])[CH:23]=3)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:8][O:7][CH2:6]1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C1COCC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C1COCC1N(C)S(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 87.2 %

Procedure:
To a slurry of 0.3 g (0.658 mmol) of 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylic acid methyl ester (Example 26, Step 1) and potassium carbonate (0.182 g, 1.32 mmol) in DMF (10 mL) was added iodomethane (0.103 g, 0.723 mmol). The reaction was stirred at 25° C. for 19 h. The DMF was removed in vacuo and the resulting oil was diluted with ethyl acetate (100 mL). The organics were washed with water (2×30 mL) and saturated aqueous sodium chloride (30 mL). The organic layer was dried over MgSO4, filtered and concentrated to provide a crude oil (0.42 g) that was purified by Biotage Flash 40S chromatography, eluting with 2:1 ethyl acetate:hexanes, to afford 4-{methyl-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl]-amino}-tetrahydro-furan-3-carboxylic acid methyl ester as an amorphous white solid (0.270 g, 87%). MS: 471 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([CH3:32])[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]2[C:16]3[N:17]([CH:24]=[C:25]([C:27]([OH:29])=O)[CH:26]=3)[N:18]=[CH:19][C:20]=2[C:21](=[O:23])[NH2:22])[C:10]1([CH3:31])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.[N:40]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=[N:41]1.NN.CCOC(C)=O>CN(C=O)C>[C:21]([C:20]1[CH:19]=[N:18][N:17]2[CH:24]=[C:25]([C:27]([NH:40][NH2:41])=[O:29])[CH:26]=[C:16]2[C:15]=1[NH:14][C@@H:11]1[CH2:12][CH2:13][C@@:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:32])[C:10]1([CH3:31])[CH3:30])(=[O:23])[NH2:22]
Reactant: CC(C)(C)OC(=O)N[C@@]1(C)CC[C@@H](Nc2c(C(N)=O)cnn3cc(C(=O)O)cc23)C1(C)C
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@]1(C)CC[C@@H](Nc2c(C(N)=O)cnn3cc(C(=O)NN)cc23)C1(C)C
Yield: 106.4 %

Procedure:
A solution of 4-(((1R,3S)-3-((tert-butoxycarbonyl)amino)-2,2,3-trimethylcyclopentyl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylic acid (3.0 g, 6.73 mmol), BOP (3.57 g, 8.08 mmol) and hydrazine (1.057 mL, 33.7 mmol) in DMF (25 mL) was stirred for 30 minutes, and then the reaction mixture was added 350 mL of EtOAc which was washed with 10% LiCl solution (2×100 mL), 100 mL of brine and dried over Na2SO4. Filtration and concentration gave the desired tert-butyl ((1S,3R)-3-((3-carbamoyl-6-(hydrazinecarbonyl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-1,2,2-trimethylcyclopentyl)carbamate (3.29 g, 99% yield). HPLC retention time=2.457 min., LC/MS (M+H)+=460.4.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([S:11]([NH2:14])(=[O:13])=[O:12])[C:5]=2[O:4][CH2:3][CH2:2]1.C[Al](C)C.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:28][C:29](=O)[O:30]C)[N:22]=1.O>C(Cl)Cl.Cl.C(O)(=O)C>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:28][C:29]([NH:14][S:11]([C:10]2[C:5]3[O:4][CH2:3][CH2:2][O:1][C:6]=3[CH:7]=[CH:8][CH:9]=2)(=[O:12])=[O:13])=[O:30])[N:22]=1
Reactant: NS(=O)(=O)c1cccc2c1OCCO2
Reactant: COC(=O)Nc1nc(C)cc(OC)n1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc3c2OCCO3)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1.0 g 1,4-benzodioxan-5-sulfonamide, prepared in Example 15, in 50 ml methylene chloride at ambient temperature under nitrogen was added 2.5 ml trimethylaluminum (2M in toluene). After stirring 15 minutes at ambient temperature, 1.0 g of methyl [4-methoxy-6-methylpyrimidin-2-yl]carbamate, prepared according to the procedure of Example 3, was added and the reaction mixture was heated at reflux for 72 hours. The reaction mixture was cooled to ambient temperature and 75 ml water, 10 ml glacial acetic acid and 10 drops hydrochloric acid were sequentially added. The organic phase was separated, dried, and the solvent removed under reduced pressure to give an oil. Crystallization of the oil from n-butyl chloride/ether gave a solid, m.p. 203°-205° C. IR(mull) 1700 (c=o) cm-1.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[N:15]([C:16]([N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[CH2:14][C:13]2[N:26]=[CH:27][N:28]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:12]=2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:36]N1C(=O)CCC1=O>C(Cl)Cl>[Br:36][C:27]1[N:28]([CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:12]2[CH2:11][C@@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])[N:15]([C:16]([N:18]([CH3:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:17])[CH2:14][C:13]=2[N:26]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(C(=O)N1Cc2ncn(Cc3ccccc3)c2C[C@H]1CO[Si](C)(C)C(C)(C)C)c1ccccc1
Solvent: ClCCl
Product: CN(C(=O)N1Cc2nc(Br)n(Cc3ccccc3)c2C[C@H]1CO[Si](C)(C)C(C)(C)C)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 1.23 g of (S)-1,4,6,7-tetrahydro-6-(t-butyldimethylsilyloxymethyl)-N-methyl-N-phenyl-1-(phenylmethyl)-5H-imidazo[4,5-c]pyridine-5-carboxamide and 10 mL of methylene chloride is stirred at room temperature and 0.45 g of N-bromosuccinimide is added. The reaction mixture is stirred for 20 min and concentrated. The residue is purified by flash chromatography on silica gel eluting with a 50% ethyl acetate-hexane mixture. The desired fractions are combined and concentrated to afford the desired product as an oil; TLC (SiO2) 50% EtOHc/hexane, Rf =0.35.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[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.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>CN(C)C=O>[CH3:21][N:22]([CH:24]=[C:9]([C:10]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=1)[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:18])[CH3:23]
Reactant: CSc1ccc(CC(=O)c2ccc(F)cc2)cc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CSc1ccc(C(=CN(C)C)C(=O)c2ccc(F)cc2)cc1
Temperature: 75 °C

Procedure:
To a 500 ml 2-necked flask fitted with a thermometer and magnetic stirrer was added 20 g (76.9 mMol) of 1-(4-fluorophenyl)-2-(4-(methylthio)phenyl)ethan-1-one, Example 1, Step 3, 18.3 g (154 mMol) of dimethylformamide dimethyl acetal and 50 ml dry dimethylformamide (DMF). The reaction mixture was heated to 75° C. for 3 hours, cooled to room temperature and evaporated to dryness and to recover 26.1 g a yellowish orange solid.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][CH2:8][NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([C:39]3[CH2:40][CH2:41][N:42]([CH2:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[CH2:43][CH:44]=3)([CH3:38])[CH3:37])[NH:13]2)=[O:11])[CH2:4][O:3]1.Cl>O1CCCC1>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][CH2:8][NH:9][C:10]([CH:12]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])[C:15]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([C:39]2[CH2:44][CH2:43][N:42]([CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:41][CH:40]=2)([CH3:38])[CH3:37])[NH:13]1)=[O:11]
Reactant: CC1(C)OC[C@H](CCNC(=O)C2NC(CC(C)(C)C3=CCN(Cc4ccccc4)CC3)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)O1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F)C1=CCN(Cc2ccccc2)CC1
Yield: 32.4 %

Procedure:
In a manner similar to the method described in Examples 42d, rac-(2R,3S,4R,5S)-5-[2-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-propyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-amide prepared in Example 127d (1 g, 1.3 mmol) was reacted with aqueous HCl solution (1 N, 5 mL, 5 mol) in tetrahydrofuran (5 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-5-[2-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-propyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.3 g, 32%).