Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C@@H:7]2[CH2:11][C@H:10]([S:12][C:13]3[C@H:19]([CH3:20])[C@H:18]4[N:15]([C:16](=[O:24])[C@@H:17]4[C@H:21]([OH:23])[CH3:22])[C:14]=3[C:25]([O:27]CC3C=CC([N+]([O-])=O)=CC=3)=[O:26])[CH2:9][N:8]2C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[N:6]=1.P([O-])([O-])([O-])=O.[H][H]>[OH-].[OH-].[Pd+2].O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C@@H:7]2[CH2:11][C@H:10]([S:12][C:13]3[C@H:19]([CH3:20])[C@H:18]4[N:15]([C:16](=[O:24])[C@@H:17]4[C@H:21]([OH:23])[CH3:22])[C:14]=3[C:25]([OH:27])=[O:26])[CH2:9][NH:8]2)[N:6]=1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](c4csc(N)n4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reactant: [H][H]
Agent: [Pd+2]
Agent: O=P([O-])([O-])[O-]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](c4csc(N)n4)C3)[C@H](C)[C@H]12
Yield: 45.7 %

Procedure:
A mixture of 4-nitrobenzyl (4R,5S,6S)-3-[(2S,4S)-2-(2-aminothiazol-4-yl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (900 mg), 20% palladium hydroxide on carbon (350 mg), 0.05M phosphate buffer (pH 6.5, 20 ml) and tetrahydrofuran (30 ml) was stirred at room temperature for 3 hours under atmospheric pressure of hydrogen. After the catalyst was filtered off, the filtrate was concentrated to remove the organic solvent. The residue was washed with ethyl acetate, adjusted to pH 6.2 with aqueous potassium carbonate and concentrated in vacuo to remove the organic solvent. The residue was chromatographed on nonionic adsorption resin "Diaion HP-20" (Trademark, made by Mitsubishi Chemical Industries) (60 ml) eluting in turn with water (250 ml) and 5-7% aqueous acetone (200 ml). The fractions containing the desired compound were collected and lyophilized to give (4R,5S,6S)-3-[(2S,4S)-2-(2-aminothiazol-4-yl) pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (233 mg).
Reaction SMILES: Cl.[CH3:2][Si:3]([C:6]#[C:7][C:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=1)([CH3:5])[CH3:4].[CH3:14][C@@:15]1([CH2:22][S:23](Cl)(=[O:25])=[O:24])[C:19](=[O:20])[NH:18][C:17](=[O:21])[NH:16]1.C(N(C(C)C)C(C)C)C>C1COCC1>[CH3:14][C@:15]1([CH2:22][S:23]([N:11]2[CH2:10][CH:9]=[C:8]([C:7]#[C:6][Si:3]([CH3:4])([CH3:5])[CH3:2])[CH2:13][CH2:12]2)(=[O:25])=[O:24])[NH:16][C:17](=[O:21])[NH:18][C:19]1=[O:20]
Reactant: C[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Reactant: C[Si](C)(C)C#CC1=CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@]1(CS(=O)(=O)N2CC=C(C#C[Si](C)(C)C)CC2)NC(=O)NC1=O
Temperature: -10 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
4-[(Trimethylsilyl)ethynyl]-1,2,3,6-tetrahydropyridine hydrochloride (3.43 g, 15.9 mmol) was stirred in THF (100 mL) with [(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride (3.39 g, 15 mmol) and cooled in an ice salt bath (temperature about −10° C.). N-Ethyldiisopropylamine (5.13 mL, 30 mmol) in THF (100 mL) was added dropwise over 2 hours and the mixture stirred a further 2 hours. The reaction mixture was washed with water, the aqueous layer extracted into EtOAc (×2), the organic phases combined, washed with 2M HCl (×2), saturated bicarbonate solution (×2), followed by brine, dried (sodium sulphate) and evaporated to give the crude product (5.06 g). This was used without further purification.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[Cl:16][C:17]1[C:18]([O:36][CH3:37])=[C:19]([C:32](=O)[CH2:33][CH3:34])[CH:20]=[C:21]2[C:26]=1[O:25][C:24]([CH3:28])([CH3:27])[CH:23]=[C:22]2[CH:29]([CH3:31])[CH3:30]>>[Cl:16][C:17]1[C:18]([O:36][CH3:37])=[C:19](/[C:32](/[CH2:33][CH3:34])=[C:6](/[F:7])\[C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:20]=[C:21]2[C:26]=1[O:25][C:24]([CH3:28])([CH3:27])[CH:23]=[C:22]2[CH:29]([CH3:30])[CH3:31]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CCC(=O)c1cc2c(c(Cl)c1OC)OC(C)(C)C=C2C(C)C
Product: CCOC(=O)/C(F)=C(/CC)c1cc2c(c(Cl)c1OC)OC(C)(C)C=C2C(C)C

Procedure:
Following General Procedure K, triethyl-2-fluoro-2-phosphonoacetate (0.4 mL, 2.14 mmol) and 1-(8-chloro-4-isopropyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-propan-1-one (Compound 140, 229 mg, 0.71 mmol) were reacted to give the title compound as a yellow oil after purification by flash chromatography (silica gel, 1:9 ethyl acetate/hexane).
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:19])[N:6]([CH2:16][CH2:17][CH3:18])[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:9]=1)([O-])=O.[H][H]>[Ni].CN(C)C=O>[NH2:1][C:4]1[C:5](=[O:19])[N:6]([CH2:16][CH2:17][CH3:18])[CH:7]=[C:8]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)[CH:9]=1
Reactant: [H][H]
Reactant: CCCn1cc(-c2ccncc2)cc([N+](=O)[O-])c1=O
Agent: [Ni]
Solvent: CN(C)C=O
Product: CCCn1cc(-c2ccncc2)cc(N)c1=O
Reaction time: 6 h

Procedure:
A solution containing 15.1 g. of 3-nitro-1-n-propyl-5-(4-pyridinyl)-2(1H)-pyridinone in 400 ml. of dry dimethylformamide was charged into an 800 ml. Parr bottle with 1.5 teaspoons of Raney nickel and the mixture was shaken under 650 p.s.i of hydrogen at room temperature for four hours, during which time the reaction temperature was no more than 50° C. The catalyst was filtered off; the filtrate was treated with decolorizing charcoal and filtered; and, the solvent was distilled off under reduced pressure to leave 12.7 g. of crystalline solid. The solid was recrystallized from methanol to yield 7.2 g. of crystalline 3-amino-1-n-propyl-5-(4-pyridinyl)-2(1H)-pyridinone, m.p. 171°-173° C. after drying at 70° C. and 0.001 mm. for six hours.
Reaction SMILES: [C:1]([O:4][C@H:5]([C:7]1[O:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][CH:18]=[C:17](Br)[C:16]=3[CH:21]=2)=[N:10][N:11]=1)[CH3:6])(=[O:3])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1B(O)O>>[C:1]([O:4][C@H:5]([C:7]1[O:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][CH:18]=[C:17]([C:28]4[CH:27]=[C:26]([F:29])[CH:25]=[CH:24][C:23]=4[Cl:22])[C:16]=3[CH:21]=2)=[N:10][N:11]=1)[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H](C)c1nnc(-c2ccc3occ(Br)c3c2)o1
Reactant: OB(O)c1cc(F)ccc1Cl
Product: CC(=O)O[C@@H](C)c1nnc(-c2ccc3occ(-c4cc(F)ccc4Cl)c3c2)o1
Yield: 66 %

Procedure:
In the same manner as in Reference Example 19 and using (1S)-1-[5-(3-bromo-1-benzofuran-5-yl)-1,3,4-oxadiazol-2-yl]ethyl acetate instead of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate and (2-chloro-5-fluorophenyl)boronic acid instead of (4-methoxyphenyl)boronic acid, the title compound (yield 66%) was obtained as colorless crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([CH3:41])[C:17]3[N:18]([C:20]([N:25]([C:27]4[S:28][C:29]([C:39]#[N:40])=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=5)[N:31]=4)[CH3:26])=[C:21]([CH2:23][CH3:24])[N:22]=3)[CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>CO>[CH2:23]([C:21]1[N:22]=[C:17]2[C:16]([CH3:41])=[CH:15][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:19][N:18]2[C:20]=1[N:25]([CH3:26])[C:27]1[S:28][C:29]([C:39]#[N:40])=[C:30]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[N:31]=1)[CH3:24]
Reactant: CCc1nc2c(C)cc(N3CCN(C(=O)OC(C)(C)C)CC3)cn2c1N(C)c1nc(-c2ccc(F)cc2)c(C#N)s1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CCc1nc2c(C)cc(N3CCNCC3)cn2c1N(C)c1nc(-c2ccc(F)cc2)c(C#N)s1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 4-(3-{[5-Cyano-4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-6-yl)-piperazine-1-carboxylic acid tert-butyl ester (24.4 g, 42 mmol, 1 eq.) in MeOH (100 mL) was added a 2 M HCl solution in Et2O (127 mL, 254 mmol, 6 eq.). The reaction mixture was stirred at r.t. for 3.5 h then concentrated in vacuo. The residue was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc. A 2 M NaOH solution was added to the aqueous layer until pH reached 8-9 and further extraction with EtOAc was performed. The combined organic layers were then washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The solid was triturated with heptane (100 mL) at r.t. overnight, filtered off, washed with heptane and Et2O, and dried to afford the expected compound.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@@H:5]1[C@:13]2([CH3:14])[C@H:8]([C@@H:9]([OH:15])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)[CH3:4].[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>ClCCl.N1C=CC=CC=1>[C:16]([O:1][CH2:2][C@@H:3]([C@@H:5]1[C@:13]2([CH3:14])[C@H:8]([C@@H:9]([OH:15])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)[CH3:4])(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C[C@@H](CO)[C@H]1CC[C@H]2[C@@H](O)CCC[C@]12C
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H](COC(=O)C(C)(C)C)[C@H]1CC[C@H]2[C@@H](O)CCC[C@]12C
Temperature: 0 °C

Procedure:
The compound of Example 3D (0.58 g, 2.7 mmol) was dissolved in 4 mL of dichloromethane and 2 mL of pyridine; the solution was cooled to 0° C., and 0.39 mL of pivaloyl chloride was added dropwise over 5 minutes. The resultant mixture was stirred at 0° C. for 2.5 hours, then it was quenched with water, and the mixture was concentrated in vacuo with the bath maintained below ambient temperature. The crude material was partitioned between ether and 0.5 N aqueous HCl; the organic phase was washed with 0.5 N aqueous HCl, then brine, and dried over Na2SO4. The solvents were removed in vacuo; the residue (0.96 g) was carried forward without further purification.
Reaction SMILES: C(OC([N:8]1[C:12]([NH:13][C:14](=[O:30])[CH:15]([CH3:29])[CH2:16][CH2:17][CH2:18][N:19]2[CH2:25][CH2:24][CH2:23][N:22]([C:26](=[O:28])[CH3:27])[CH2:21][CH2:20]2)=[CH:11][C:10]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[N:9]1)=O)(C)(C)C.Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([C:10]2[CH:11]=[C:12]([NH:13][C:14](=[O:30])[CH:15]([CH3:29])[CH2:16][CH2:17][CH2:18][N:19]3[CH2:25][CH2:24][CH2:23][N:22]([C:26](=[O:28])[CH3:27])[CH2:21][CH2:20]3)[NH:8][N:9]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(-c2cc(NC(=O)C(C)CCCN3CCCN(C(C)=O)CC3)n(C(=O)OC(C)(C)C)n2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(-c2cc(NC(=O)C(C)CCCN3CCCN(C(C)=O)CC3)[nH]n2)cc1
Yield: 82.6 %

Procedure:
5-[5-(4-Acetyl-[1,4]diazepan-1-yl)-2-methyl-pentanoylamino]-3-(4-methoxy-phenyl)-pyrazole-1-carboxylic acid tert-butyl ester (181.0 mg, 0.34 mmol, 1.0 eq) was dissolved in DCM (3 mL) and HCl 4.0 M in dioxane (0.16 mL, 0.64 mmol, 1.9 eq) was added at room temperature. After 3 hours another 1.9 eq of HCl was added and the mixture stirred for 3 additional hours. NaHCO3 saturated solution was added and the organic layer collected and dried. Evaporation of solvent gave the title product (120 mg; Yield 82%).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:29]=[CH:28][C:11]([C:12]([O:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=2)=O)=O)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([NH2:33])(=O)C.B(F)(F)F>>[CH2:1]([O:7][C:8]1[CH:29]=[CH:28][C:11]([C:12]2[O:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=3)[N:33]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(N)=O
Reactant: CCCCCCOc1ccc(C(=O)OCC(=O)c2ccc(C(=O)OC)cc2)cc1
Agent: FB(F)F
Product: CCCCCCOc1ccc(-c2nc(-c3ccc(C(=O)OC)cc3)co2)cc1
Temperature: 140 °C
Reaction time: 18 h
Yield: 18 %

Procedure:
140 mg (0.377 mmol) 2-[4-(methoxycarbonyl)phenyl]-2-oxoethyl 4-hexyloxybenzoate and 111 mg (5 eq) acetamide were dissolved in 5 mL xylenes. 10 uL (0.2 eq) boron trifluoride was added and the reaction was stirred at 140° C. for 18 h. Another 50 uL (1.0 eq) boron trifluoride was added and stirring continued for 24 h. The reaction was quenched with saturated sodium bicarbonate solution and extracted with DCM. The combined organic phases were dried and evaporated. Purification of the residue by flash chromatography (100% hexanes to 10% EA/hexanes) yielded 26 mg (0.068 mmol, 18%) of the product. MS: m/z=380.21 [M+1]+.
Reaction SMILES: [NH2:1][C@@:2]([CH3:8])([CH2:6][OH:7])[C:3]([OH:5])=[O:4].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([NH:1][C@@:2]([CH3:8])([CH2:6][OH:7])[C:3]([OH:5])=[O:4])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@](N)(CO)C(=O)O
Reactant: O=Cc1ccccc1
Product: C[C@@](CO)(NCc1ccccc1)C(=O)O
Yield: 50.2 %

Procedure:
(S)-2-amino-3-hydroxy-2-methylpropanoic acid (1.2 g, 10 mmol) was reacted with benzaldehyde (1.06 g, 10 mmol) according to the procedure as described in Example 46, Step A to give the title compound as a gray solid (1.05 g, 50%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][NH:10][C:11]([NH:13][CH2:14][CH2:15][O:16][CH3:17])=[O:12])=O)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:13]([CH2:14][CH2:15][O:16][CH3:17])[C:11](=[O:12])[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COCCNC(=O)NNC(=O)c1ccc(Cl)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COCCn1c(-c2ccc(Cl)s2)n[nH]c1=O

Procedure:
4.85 g (17.46 mmol) of the compound of Example 49A were dissolved in 17 ml (52.39 mmol) of 3 M aqueous sodium hydroxide solution and heated under reflux for 168 h. After 16, 40, 64 and 88 h, in each case a further 1.05 g (26.19 mmol, 104.76 mmol in total) of solid sodium hydroxide were added. Using 1M hydrochloric acid, the reaction was adjusted to pH 10, and the mixture was extracted twice with in each case 30 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and freed from the solvent on a rotary evaporator. The residue was dried under high vacuum. This gave 2.44 g (54% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:20]=[C:19]([C:21]([NH2:23])=O)[O:18][N:17]=4)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCOCC1>[F:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:20]=[C:19]([C:21](=[S:35])[NH2:23])[O:18][N:17]=4)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1
Reactant: NC(=O)c1cc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)no1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: NC(=S)c1cc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)no1
Yield: 81 %

Procedure:
To a solution of 3-[4-(6-fluoro-benzothiazol-2-ylamino)-phenyl]-isoxazole-5-carboxylic acid amide (3.54 g; 10 mmol) in dioxane (25 ml), was added Lawesson's reagent (4.11 g; 10 mmol) and the resulting reaction mixture was refluxed for 45 min. The pH of the reaction mixture was adjusted to near neutral, the solvent was removed and the residue was diluted with water (20 ml) and extracted with EtOAc (3×30 ml). The EtOAc layer was washed with water (3×10 ml) followed by brine (10 ml), and dried over anhydrous Na2SO4. The solvent was removed, and the residue was triturated with dichloromethane, filtered and dried to afford 3.0 g (80%) of the title compound. Mass (ES−), 369 (M−1); IR (KBr): 3282 (br), 3142 (br), 1651, 1608, 1588, 1555, 1441 (br); 1H NMR (DMSO-d6) δ: 7.18 (m, 1H), 7.58 (s, 1H), 7.65 (m, 1H), 7.77 (m, 1H), 7.88-7.94 (br, 4H), 7.97, 10.33 (2×br, 2H), 10.79 (s, 1H).
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13](O)=[O:14])[CH2:7][CH2:6]1)(=[NH:4])[NH2:3].[Cl:16]C1C=CC(OS([O:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=O)=CC=1.CN(C)C=O>N1C=CC=CC=1>[ClH:16].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:26][C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[O:14])[CH2:7][CH2:6]1)(=[NH:3])[NH2:4]
Reactant: O=S(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1
Reactant: N=C(N)N1CCC(CCC(=O)O)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: N=C(N)N1CCC(CCC(=O)Oc2ccc(Cl)cc2)CC1
Yield: 79.4 %

Procedure:
A mixture of 1.5 g of 1-amidino-4-piperidinepropionic acid hydrochloride and 7.7 g of bis-(p-chlorophenyl)sulfite was stirred at room temperature for 30 minutes in a solution of 12 ml of dry dimethylformamide and 6 ml of dry pyridine. The solvent was removed under reduced pressure, and ether was added to the residue to give crystals. The crystals were washed with ether twice and then with ethyl acetate and recrystallized from methanol-ether to obtain 1.75 g (yield: 79.5%) of p-chlorophenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 173° to 176° C.
Reaction SMILES: [NH2:1][C@@:2]1([CH2:9][C:10]#[C:11][C:12]2[N:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:13]=2)[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[O:8]>CC#N.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH3:7][N:4]1[CH2:5][CH2:6][C@:2]2([N:1]=[C:11]([C:12]3[N:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=4)[N:13]=3)[CH2:10][CH2:9]2)[C:3]1=[O:8]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C#CC[C@]2(N)CCN(C)C2=O)n1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C2=N[C@@]3(CC2)CCN(C)C3=O)n1
Reaction time: 72 h
Yield: 92.6 %

Procedure:
Silver trifluoromethanesulphonate (358.56 mg, 1.4 mmol) was added to a solution of (3S)-3-amino-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]pyrrolidin-2-one (2.71 g, 6.98 mmol) (which may be prepared as described in Description 14a) in MeCN (60 mL) at 50° C. and the reaction was stirred for 3 days. Additional AgOTf (10 mol %) was added and stirring was continued for 24 hrs. The solvent was evaporated and the residue was suspended in EtOAc. The organics were washed with water, dried (Na2SO4) and the solvent evaporated to afford a light brown oil. This was purified using a Biotage Isolera with a 100 g SNAP cartridge, eluting with 0 to 100% (mixture of 1% of 2M NH3 in MeOH; 9% MeOH; 90% EtOAc) in EtOAc, affording the (5S)-7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]non-1-en-6-one (D15a) (2.51 g, 6.4626 mmol, 92.6% yield) as a light brown solid. The NMR was the same is as that for the R isomer produced in Description 15 but also contained traces of impurities.
Reaction SMILES: F[C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[C:5](C(F)(F)F)=[CH:4][CH:3]=1.IC1SC2C=CC=C([O:43][C:44]([F:47])([F:46])[F:45])C=2N=1>>[NH:25]1[CH2:26][CH2:27][CH:22]([N:20]2[CH:21]=[C:17]([C:15]3[CH:16]=[C:11]([C:8]4[S:9][C:10]5[CH:2]=[CH:3][CH:4]=[C:5]([O:43][C:44]([F:47])([F:46])[F:45])[C:6]=5[N:7]=4)[C:12]([NH2:28])=[N:13][CH:14]=3)[CH:18]=[N:19]2)[CH2:23][CH2:24]1
Reactant: FC(F)(F)Oc1cccc2sc(I)nc12
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)ccc(F)c2s1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(OC(F)(F)F)cccc2s1

Procedure:
Following the procedure for 3-(7-fluoro-4-trifluoromethylbenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine, using 2-iodo-4-trifluoromethoxy-1,3-benzothiazole and conducting the Suzuki coupling at 50° C. for 12 h, the title compound was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=9.12-9.03 (brm, 1H), 8.94-8.82 (brm, 1H), 8.57 (d, J=2.0 Hz, 1H), 8.41 (brs, 2H), 8.34 (very brs, 2H), 8.26 (dd, J=2.2, 6.6 Hz, 1H), 8.07 (s, 1H), 7.66-7.60 (m, 2H), 4.57-4.48 (mc, 1H), 3.41 (brd, J=12.8 Hz, 2H), 3.11 (brq, J=11.2 Hz, 2H), 2.30-2.12 (m, 4H). MS(ES+): m/z=461.06 (74) [MH+], 378.06 (100) [MH+-piperidine]. HPLC: tR=2.27 min (polar—5 min, ZQ2).
Reaction SMILES: Br[C:2]([F:44])([F:43])[C:3](F)([F:41])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34](F)([F:39])[C:35]([F:38])([F:37])Br)=[CH:29][CH:28]=2)([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20](F)([F:25])[C:21]([F:24])([F:23])Br)=[CH:15][CH:14]=2)[CH3:12])=[CH:7][CH:6]=1>C(#N)C>[F:25][C:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][C:3]([F:41])=[C:2]([F:43])[F:44])=[CH:10][CH:9]=2)([C:27]2[CH:28]=[CH:29][C:30]([O:33][C:34]([F:39])=[C:35]([F:37])[F:38])=[CH:31][CH:32]=2)[CH3:12])=[CH:14][CH:15]=1)=[C:21]([F:24])[F:23]
Reactant: CC(c1ccc(OC(F)(F)C(F)(F)Br)cc1)(c1ccc(OC(F)(F)C(F)(F)Br)cc1)c1ccc(OC(F)(F)C(F)(F)Br)cc1
Solvent: CC#N
Product: CC(c1ccc(OC(F)=C(F)F)cc1)(c1ccc(OC(F)=C(F)F)cc1)c1ccc(OC(F)=C(F)F)cc1

Procedure:
A sample of impure tris-perfluorovinyl ether ("tris") (180.8 g, 93.5% tris-, 6.5% bis-perfluorovinyl ether; purity as determined by gas chromotography corresponding to mole percent) is diluted with 1500 mL of hexane to make an approximately 10% (by volume) solution. The pumps are started, with hexane pumped into the bottom of the column (above the acetonitrile take-off) and acetonitrile pumped into the top of the column (below the hexane take-off). The flow rates are adjusted to 90 mL/min for hexane and 45 mL/min for acetonitrile. The hexane reservoir is allowed to drain until nearly empty, and the solution of impure tris-perfluorovinyl ether is transferred to the reservoir. After this is transferred onto the column, the reservoir is filled again with 1500 mL of hexane (saturated with acetonitrile). This is allowed to pump through the column and into the product reservoir to ensure complete washing of the product from the column. The hexane solution which exits the column contains tris-perfluorovinyl ether (99.5% purity, 49% recovery). The acetonitrile solution which exits the column contains the remainder of the product (88.35 g, 85.5% tris- and 14.5% bis-perfluorovinyl ether) and is concentrated by rotary evaporation, rediluted in hexane (750 mL) and purified by running it through the countercurrent extractor to give 50.55 g of tris-perfluorovinyl ether (98.2% purity). The acetonitrile solution from this pass contains 25.7 g of material which is 71% tris- and 28.5% bis-perfluorovinyl ether. The ether is found to have the following properties:
Reaction SMILES: [C:1]([NH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([OH:21])=O)[CH2:15][CH2:14]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(Cl)([Cl:24])=O>CCCCC>[C:1]([NH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([Cl:24])=[O:21])[CH2:15][CH2:14]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CCCCC
Product: O=C(NC[C@H]1CC[C@H](C(=O)Cl)CC1)OCc1ccccc1
Temperature: 40 °C

Procedure:
A mixture of trans-4-(N-carbobenzyloxy)aminomethyl-1-cyclohexane carboxylic acid (5.02 g, 17.3 mmol), prepared as in step 1, and thionyl chloride was heated at 40° C. for 30 minutes. The reaction mixture was cooled to ambient temperature and diluted with pentane (50 mL). Trans-4-(N-carbobenzyloxy)aminomethyl-1-cyclohexane carbonyl chloride (4.37 g) was isolated by filtration and drying in vacuo.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>CO.C(Cl)Cl.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Reaction time: 8 h
Yield: 72 %

Procedure:
1 equiv of 43 dissolved in methanol (anhydrous) and 10% of 10% Pd/C was added under a hydrogen atmosphere and allowed to stir overnight at room-temp. Reaction was filtered through a pad of celite and concentrated to give a blue/purple oil. The oil was brought up in DCM acidified using 1 M HCl and organic wash was removed. The aqueous was neutralized with sat'd sodium bicarbonate and washed 3 times with DCM, dried with sodium sulfate, filtered and concentrated and resulted in a pale red oil, 72% yield. MS (ES) 277.8 [MH+].