Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][N:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>CO.C(OCC)(=O)C>[S:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[C:2]([NH:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:3]1
Reactant: NCCCN
Reactant: Brc1nsc2ncccc12
Solvent: CO
Solvent: CCOC(C)=O
Product: NCCCNc1nsc2ncccc12
Temperature: 64 °C

Procedure:
A mixture of 3-bromoisothiazolo[5,4-b]pyridine (1.9 g, 8.8 mmol), and 1,3-diaminopropane (6.7 g, 90 mmol) in methanol (10 ml) was heated at 64° C. for 1.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Lyophilization of the crude sample in acetonitrile/water mixture yielded N1-(isothiazolo[5,4-b]pyridin-3-yl)propane-1,3-diamine. 1H NMR (300 MHz, DMSO-d6): 8.68 (d, 1H), 8.53 (d, 1H), 7.73 (br s, 1H), 7.40 (dd, 1H), 3.46 (dd, 2H), 2.85 (t, 2H), 1.75 (t, 2H), 1.45 ppm (t, 2H). MW=208 confirmed by LC-MS, tr=5.55 min (Method Y) MH+=209.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:20][C@H:19]([CH3:21])[C@@H:18]([OH:22])[CH2:17][C:15](=[O:16])[O:14][C@H:13]([C@H:23]2[C@H:27]([C:28]([OH:30])=[O:29])[CH2:26][CH2:25][CH2:24]2)[CH2:12][CH:11]=[CH:10][CH:9]=[C:8]([C:31]#[N:32])[C@H:7]([OH:33])[C@@H:6]([CH3:34])[CH2:5][C@H:4]([CH3:35])[CH2:3]1.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][NH2:43])[CH:37]=1>C(Cl)(Cl)Cl.CO>[CH3:1][C@@H:2]1[CH2:20][C@H:19]([CH3:21])[C@@H:18]([OH:22])[CH2:17][C:15](=[O:16])[O:14][C@H:13]([C@H:23]2[C@H:27]([C:28]([OH:30])=[O:29])[CH2:26][CH2:25][CH2:24]2)[CH2:12][CH:11]=[CH:10][CH:9]=[C:8]([C:31]#[N:32])[C@H:7]([OH:33])[C@@H:6]([CH3:34])[CH2:5][C@H:4]([CH3:35])[CH2:3]1.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][NH-:43])[CH:37]=1
Reactant: NCc1cccnc1
Agent: C[C@@H]1C[C@H](C)C[C@H](C)[C@@H](O)CC(=O)O[C@H]([C@@H]2CCC[C@H]2C(=O)O)C/C=C/C=C(/C#N)[C@H](O)[C@@H](C)C1
Agent: C[C@@H]1C[C@H](C)C[C@H](C)[C@@H](O)CC(=O)O[C@H]([C@@H]2CCC[C@H]2C(=O)O)CC=CC=C(C#N)[C@H](O)[C@@H](C)C1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: [NH-]Cc1cccnc1
Reaction time: 3 h

Procedure:
To a mixed anhydride solution prepared from 4.0 g (8.2 mmol) of borrelidin according to Example 34.2 ml (41.2 mmol, 4.46 g) of 3-picolylamine were added. After stirring for 3 hours, the starting borrelidin (Rf=0.43) disappeared and the product (Rf=0.24) appeared, which was proved by thin-layer chromatography (silica gel plate, eluent system: chloroform/methanol 95:5). The reaction mixture was evaporated to dryness. The dry residue was dissolved in 500 ml of chloroform, washed with 3×1500 ml of water, dried over sodium sulfate and evaporated to dryness. The dry residue was chromatographed on a silica gel column with mixtures of chloroform and ethyl acetate of increasing ethyl acetate content. The fractions containing the product eluting with a 2:8 eluting mixture were combined and evaporated to dryness. To the thus-obtained solidifying oily substance (3.62 g) 4 ml of ethyl acetate and 20 ml of n-hexane were added, the solid material was triturated and then filtered. In this way 3.04 g product were obtained. Mp.: 99-105° C.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2([OH:25])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1>>[OH:25][C:19]1([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[CH:14]=2)[CH2:24][CH2:23][CH2:22][N:21]([C:6]([C:5]2[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=2)=[O:7])[CH2:20]1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Product: COc1cccc(C2(O)CCCN(C(=O)c3ccc(I)cc3)C2)c1

Procedure:
The compound of Example 31 was prepared according to the general preparation protocol A from 4-iodobenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][CH:30]=[CH:29][C:4]=1[O:5][CH2:6][CH2:7][NH:8][CH2:9][CH:10]([C:18]1[CH:19]=[CH:20][C:21]([CH3:28])=[C:22]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:23]=1)[S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH:33]O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:32]=[CH:31][CH:30]=[CH:29][C:4]=1[O:5][CH2:6][CH2:7][NH:8][CH2:9][CH:10]([C:18]1[CH:19]=[CH:20][C:21]([CH3:28])=[C:22]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:23]=1)[S:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:33]
Reactant: OO
Reactant: COc1ccccc1OCCNCC(Sc1ccccc1)c1ccc(C)c(S(N)(=O)=O)c1
Solvent: CC(=O)O
Product: COc1ccccc1OCCNCC(c1ccc(C)c(S(N)(=O)=O)c1)S(=O)c1ccccc1

Procedure:
In 20 ml of acetic acid was dissolved 2 g of 5-{2-[2-(2-methoxyphenoxy)ethylamino]-1-phenylthioethyl}-2-methylbenzenesulfonamide and after adding thereto 0.5 ml of 30% H2O2, the mixture was heated to 50°-60° C. for 3 hours. After adding thereto 100 ml of water, the reaction mixture was extracted with 200 ml of ethyl acetate. The ethyl acetate extract was washed with an aqueous 1% sodium carbonate solution and then ethyl acetate was distilled off under reduced pressure. The residue was applied to a silica gel column chromatography, the product was eluted with a mixed solvent of chloroform and methanol (9:1 by volume ratio), and the colorless viscous oily product thus obtained was crystallized by the addition of ethyl acetate. The crystals formed were recovered by filtration to provide 1.3 g of 5-{2-[2-(2-methoxyphenoxy)ethylamino]-1-phenylsulfinylethyl}-2-methylbenzenesulfonamide.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>CN(C=O)C>[Si:14]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
To an ice-cooled solution of hydroquinone (Compound 17; 3.3 g, 30 mmol) in DMF (60 ml), a solution of imidazole (3.1 g, 45 mmol) and tert-butyldimethylsilyl chloride (4.5 g, 30 mmol) in DMF (30 ml) was added; the ice bath was removed, and this was followed by overnight stirring at room temperature. This was poured over water to stop the reaction, after which extraction from ether was conducted. The combined organic phases were washed with saturated brine, thereafter dried with sodium sulfate. After filtration and concentration under reduced pressure, the residue obtained was purified by silica gel column chromatography [Biotage, eluent (9:1 n-hexane:ethyl acetate)] to yield Compound 18 (white solid 3.6 g, 53%).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15](Cl)=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:18]([O:22][C:23](=[O:25])[NH2:24])[CH2:19][CH2:20][CH3:21]>>[CH2:18]([O:22][C:23](=[O:25])[NH:24][C:15]([CH:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:6][C:5]2[C:14]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:16])[CH2:19][CH2:20][CH3:21]
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Reactant: CCCCOC(N)=O
Product: CCCCOC(=O)NC(=O)C1c2ccccc2Oc2ccccc21

Procedure:
The title compound, white solid, m.p.=180-183° C., MS: m/e=325.4 (M+H+) was prepared in accordance with the general method of example 6 from 9H-xanthene-9-carbonyl chloride and carbamic acid butyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23]([CH:25]=C)=[N:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:27])[O:4][N:3]=1.I([O-])(=O)(=O)=[O:29].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23]([CH:25]=[O:29])=[N:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1nc2ccc(-c3c(C)noc3C)c3c2n1[C@@H](c1ccccn1)CO3
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc(C)c1-c1ccc2nc(C=O)n3c2c1OC[C@@H]3c1ccccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 147.1 %

Procedure:
(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-vinyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (0.05 g, 0.1 mmol) was dissolved in tetrahydrofuran (1.7 mL). The resulting solution was cooled to 0° C., then a solution of 0.16 M osmium tetraoxide in water (0.3 mL, 0.04 mmol) [Aldrich, cat. #251755] and sodium metaperiodate (140 mg, 0.66 mmol) [Aldrich, cat. #S1878] in water (0.1 mL) were added. The reaction was allowed to warm to room temperature and stirred for 1 h. The reaction was quenched with saturated aqueous sodium sulfite (10 mL) for 10 min at room temperature. The mixture was filtered through a Celite plug and the plug was rinsed with dichloromethane. The organic layer was concentrated under vacuum. The resulting residue was purified by flash chromatography elucting ethyl acetate in hexanes (75-100%, ethyl acetate containing 20% MeOH) to afford the desired product (0.053 g, 100%). LCMS for C20H17O3N4 (M+H)+: calculated m/z=361.1. found 361.2.
Reaction SMILES: F[C:2]1C=CC(C2C(C)=C(O)C(=O)N(CC(C)C)N=2)=[CH:4][C:3]=1[CH3:21].[F:22][C:23]1[CH:24]=[C:25]([C:30]2[CH:31]=[C:32]([C:37]([O:39][CH3:40])=[O:38])[C:33](=[O:36])[NH:34][N:35]=2)[CH:26]=[CH:27][C:28]=1[F:29]>>[F:22][C:23]1[CH:24]=[C:25]([C:30]2[CH:31]=[C:32]([C:37]([O:39][CH3:40])=[O:38])[C:33](=[O:36])[N:34]([CH2:2][CH:3]([CH3:21])[CH3:4])[N:35]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: COC(=O)c1cc(-c2ccc(F)c(F)c2)n[nH]c1=O
Reactant: Cc1cc(-c2nn(CC(C)C)c(=O)c(O)c2C)ccc1F
Product: COC(=O)c1cc(-c2ccc(F)c(F)c2)nn(CC(C)C)c1=O

Procedure:
Following the procedure of Example 1 (6), 6-(3,4-difluorophenyl)-4-methoxycarbonyl-2H-pyridazin-3-one was reacted to yield the title compound as a yellow oil (yield: quantitative).
Reaction SMILES: C[N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.[CH3:18][C:19]1[C:23](C#N)=[C:22]([NH2:26])[NH:21][N:20]=1>C(O)(=O)C>[CH3:18][C:19]1[C:23]([C:22]#[N:26])=[C:17]2[N:2]=[CH:3][CH:4]=[C:5]([C:7]3[CH:8]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:11][CH:12]=3)[N:21]2[N:20]=1
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: Cc1n[nH]c(N)c1C#N
Solvent: CC(=O)O
Product: Cc1nn2c(-c3cccc(C(F)(F)F)c3)ccnc2c1C#N

Procedure:
A mixture of 24.3 g. of 3-dimethylamino-3'-(trifluoromethyl)acrylophenone, 150 ml. of glacial acetic acid and 12.2 g. of 3-methyl-5-aminopyrazole-4-carbonitrile is refluxed for 6 hours and then evaporated. The residue is treated as described in Example 1, giving the desired product, m.p. 149°-150° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH3:11][C:12]1[C:13]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=1>>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([N:22]2[CH2:23][CH2:24][N:19]([C:13]3[C:12]([CH3:11])=[CH:17][C:16]([CH3:18])=[CH:15][N:14]=3)[CH2:20][CH2:21]2)=[O:10])=[N:4][CH:3]=1
Reactant: O=C(O)c1ncc(Br)cn1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ncc(Br)cn3)CC2)c(C)c1
Yield: 71.9 %

Procedure:
Using 5-bromopyrimidine-2-carboxylic acid (0.81 g) and 1-(3,5-dimethylpyridin-2-yl)piperazine (0.77 g) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (1.08 g) was obtained.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][S:3]1.Cl.[CH3:11][O:12][C:13](=[O:20])[C@H:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[NH2:15]>C1COCC1>[CH3:11][O:12][C:13](=[O:20])[C@H:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[NH:15][C:7]([C@@H:5]1[CH2:4][S:3][C:2](=[O:1])[NH:6]1)=[O:9]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: O=C1N[C@H](C(=O)O)CS1
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CSC(=O)N1

Procedure:
To a solution of (R)-(−)-2-oxo-thiazolidine-4-carboxylic acid (1.49 g, 10.2 mmols), L-Leucine methylester hydrochloride (1.85 g, 10.2 mmols) and N-methylmorpholinee (1.12 ml, 10.2 mmols) in anhydrous THF (15 ml), cooled at 0° C., was added, under stirring, a solution of DCDI (2.10 g, 10.2 mmols) and HBT (13 mg, 1 mmols) in anhydrous THF (8 ml). After standing one night at room temperature, the N,N′-dicyclohexylures and the hydrochloride of N-methylmorpholines were separated by filtration and the filtered substance was concentrated at reduced pressure. The product was purified by dilution of the raw reside with CHCl3 (50 ml) and extraction with saturated NaHCO3 solution (20 ml×2) and saturated NaCl solution (30 ml). Drying of the organic phase reunited on Na2SO4 and the removal of the solvent at reduced pressure provided the N-{[(R)-(2-Oxo-thiazolidine-4-yl)carbonyl]}-L-leucine methylester which was crystallized with EtOAc: 1.94 g (69%); m.p. 125-6° C.; [a]D22=−79° (1, methanol); IR (CHCl3): 3412, 2956, 1734, 1678, 1515, 1434, 1338, 1158 cm−1; 1H-NMR (CHCl3): d 0.90 and 0.95 [two s, 6, CH2CH(CH3)2], 1.42-74 [m, 3, CH2CH(CH3)2], 3.37-3.85 [m, 2, CH2S and 3.63 (s, 3, OCH3)], 4.18-4.69 (two m, 2, aCH and ring CH), 7.16 (d, 1, NH, J=8 Hz). Calculated for C11H17N2O4S: C, 48.34; H, 6.27; N, 10.25. Found C, 48.29; H, 6.80; N, 10.22%.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17]C[CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][C:22]1[C:23](=[O:28])[NH:24][CH:25]=[CH:26][CH:27]=1.N1NC(=O)C=CC=1>>[CH:14]([N:13]([CH3:17])[C@H:11]1[CH2:12][C@H:9]([C:7]2[S:8][C:4]3[CH:3]=[C:2]([N:24]4[CH:25]=[CH:26][CH:27]=[C:22]([CH3:21])[C:23]4=[O:28])[CH:20]=[CH:19][C:5]=3[N:6]=2)[CH2:10]1)([CH3:15])[CH3:18]
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: Cc1ccc[nH]c1=O
Agent: O=c1cccn[nH]1
Product: Cc1cccn(-c2ccc3nc([C@H]4C[C@H](N(C)C(C)C)C4)sc3c2)c1=O

Procedure:
The title compound was prepared according to the procedure described in Example 22, except for substituting the product of Example 52A for the product of Example 1E and substituting 3-methyl-2-pyridone for 3(2H)-pyridazinone. 1H NMR (400 MHz, CDCl3) δ ppm 8.02 (d, J=8.59 Hz, 1H) 7.89 (d, J=1.84 Hz, 1H) 7.42 (dd, J=8.75, 1.99 Hz, 1H) 7.23-7.34 (m, 2H) 6.18 (t, J=6.75 Hz, 1H) 3.52-3.63 (m, 1H) 3.12-3.27 (m, 1H) 2.90-3.03 (m, 1H) 2.55-2.73 (m, 2H) 2.25-2.44 (m, 2H) 2.20 (s, 3H) 2.13 (s, 3H) 1.02 (d, J=6.44 Hz, 6H). MS: (M+H)+=368.
Reaction SMILES: [CH3:1][O-].[Na+].[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:17]2[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=2[NH:15][C:14](=[O:23])[C:13](=[CH:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:12]=1.CI>CN(C)C=O>[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:17]2[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=2[N:15]([CH3:1])[C:14](=[O:23])[C:13](=[CH:24][N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[N:12]=1
Reactant: O=C1Nc2ccc(F)cc2C(c2ccccc2Cl)=NC1=CN1CCOCC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)C(=CN2CCOCC2)N=C(c2ccccc2Cl)c2cc(F)ccc21
Temperature: 0 °C

Procedure:
1.6 gm of a methanolic 30% sodium methylate solution were added to a suspension of 2 gm of 5-(2'-chloro-phenyl)-1,3-dihydro-7-fluoro-3-(morpholino-methylene)-2H-1,4-benzodiazepin-2-one in 50 ml of dimethylformamide at room temperature, whereby a reddish-brown solution was immediately formed. The resulting solution was cooled to 0°C, and then 2.1 gm of methyl iodide were added dropwise thereto. After one hour the mixture was poured into ice water, and the precipitate formed thereby was collected by vacuum filtration and dried over phosphorus pentoxide, yielding the compound named in the heading, which had a melting point of 110°-115°C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([NH:24][C@H:25]([CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=1)[C:26]([NH:28][C:29]1[CH:30]=[CH:31][C:32]2[C:36]([CH3:38])([CH3:37])[O:35][B:34]([OH:39])[C:33]=2[CH:40]=1)=[O:27])=[O:23])[CH2:10][CH2:11][C:12]([O:14]CC1C=CC=CC=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.O.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([NH:24][C@H:25]([CH2:41][CH2:42][C:43]1[CH:44]=[CH:45][C:46]([C:49]([F:51])([F:52])[F:50])=[CH:47][CH:48]=1)[C:26]([NH:28][C:29]1[CH:30]=[CH:31][C:32]2[C:36]([CH3:37])([CH3:38])[O:35][B:34]([OH:39])[C:33]=2[CH:40]=1)=[O:27])=[O:23])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)Nc1ccc2c(c1)B(O)OC2(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)Nc1ccc2c(c1)B(O)OC2(C)C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of (S)-benzyl 4-(tert-butoxycarbonylamino)-5-((R)-1-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-ylamino)-1-oxo-4-(4-(trifluoromethyl)phenyl)butan-2-ylamino)-5-oxopentanoate (1.8 g, 2.48 mmol) in a mixture of EtOH/H2O (20 mL/2 mL) was added Pd(OH)2/C (cat.). The mixture was stirred under a H2 atmosphere for 2 h. The mixture was filtered through Celite and washed with MeOH. The filtrate was evaporated to dryness under vacuum to produce (S)-4-(tert-butoxycarbonylamino)-5-((R)-1-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-ylamino)-1-oxo-4-(4-(trifluoromethyl)phenyl)butan-2-ylamino)-5-oxopentanoic acid (CLXXI) as a white foam (1.57 g, 2.48 mmol, 100% yield). ESIMS found for C30H37BF3N3O3 m/z 634.6 (M−H).
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[CH:5]1([CH:11]=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.N1CCC[C@H]1C(O)=O>CN(C)C=O.C(OCC)C>[CH:5]1([C@H:11]([OH:12])[C@H:2]([CH3:3])[CH:1]=[O:4])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=CC1CCCCC1
Reactant: CCC=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C[C@H](C=O)[C@@H](O)C1CCCCC1
Reaction time: 22 h
Yield: 87 %

Procedure:
A solution of freshly distilled propionaldehyde (72 μL, 1.0 mmol) in 500 μL dimethylformamide pre-cooled to 4° C. was added slowly over the course of 20 h to a stirring suspension of cyclohexane carboxaldehyde (242 μL, 2.0 mmol), L-proline (11.5 mg, 0.10 mmol) and 500 μL dimethylformamide at 4° C. After 22 hours, the resulting solution was diluted with diethyl ether and washed successively with water and brine. The combined aqueous layers were back-extracted with 3 portions dichloromethane. The organic layers were combined, dried over anhydrous MgSO4, and concentrated in vacuo. Flash chromatography (20:7 pentane:diethyl ether) afforded the title compound as a clear, colorless oil in 87% yield (148 mg, 0.87 mmol), 99% ee and 93:7 anti:syn. IR (film) 3438, 2928, 2853, 1722, 1450, 1396, 1376, 1314, 1186, 1112, 1063, 975.8, 893.2, 847.5 cm−1; 1H NMR (300 MHz, CDCl3) δ9.75 (d, 1H, J=2.1 Hz, CHO); 3.53 (dd, 1H, J=7.2, 4.8 Hz, CHOH); 2.58 (m, 1H, CHCH3); 1.8-1.0 (br m, 11H, cyclohexyl); 1.10 (d, 3H, J=7.2 Hz, CH3); 3C NMR (75 MHz, CDCl3) δ206.1, 77.1, 49.2, 40.7, 30.3, 26.73, 26.69, 26.68, 26.4, 11.4; HRMS (CI) exact mass calcd for [M+H]+ (C10H19O2) requires m/z 171.1385, found m/z 171.1386. [α]D=−5.1 (c=1.0, CHCl3). The product ratios were determined by GLC analysis of the corresponding 4-cyclohexyl-2,2,5-trimethyl-[1,3]dioxane (obtained by NaBH4 reduction followed by acetonide protection of the 1,3-diol according to the method of Goto, in Kitamura et al. (1984) J. Am. Chem. Soc. 106:3252) using a Bodman Chiraldex β-DM (30 m×0.25 mm) column (110° C. isotherm, 23 psi); (2S, 3S) anti isomer tr=17.8 min, (2R, 3R) anti isomer tr=18.7 min, (2R, 3S) and (2S, 3R) syn isomers tr=21.0, 22.2 min.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([O:21][CH2:22][CH2:23][O:24][CH3:25])[CH:20]=1)(OC(C)(C)C)=O.[ClH:26]>C(Cl)Cl.CCOCC>[ClH:26].[ClH:26].[CH3:25][O:24][CH2:23][CH2:22][O:21][C:19]1[CH:20]=[C:15]([O:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[CH:16]=[N:17][CH:18]=1
Reactant: COCCOc1cncc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COCCOc1cncc(OC[C@@H]2CCCN2)c1
Reaction time: 2 h

Procedure:
To 3-(1-BOC-2-(S)-pyrrolidinylmethoxy)-5-methoxyethoxypyridine from step 197e (480 mg, 1.36 mmol) in CH2Cl2 at 0° C. was added a solution of HCl in Et2O, and the solution was stirred for 2 h. The solvent was removed and the residue was recrystallized from EtOH/Et2O to afford the title compound (215 mg): mp 182-184° C.; [α]25D +22.8° (c 0.56, MeOH); 1H NMR (D2O, 300 MHz) δ 1.98 (m, 1H), 2.00-2.06 (m, 2H), 2.25 (m, 1H), 3.00 (m, 1H), 3.05 (s, 3H), 3.65 (t, 2H, J=6.0 Hz), 3.85 (t, 2H, J=6.0 Hz), 4.15 (m, 1H), 4.30-4.35 (m, 2H), 4.52 (m, 1H), 7.15 (t, 1H, J=3.0 Hz), 8.02 (br s, 2H); MS (CI/NH3) m/z 253 (M+H)+, 279 (M+NH4)+ ; Anal. Calcd for C13H20N2O3.2.1 HCl: C, 47.48; H, 6.77; N, 8.52. Found: C, 47.56; H, 6.83; N, 8.51.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5](N)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[I-:21].[K+]>O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]([I:21])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nc1-c1ncccc1F
Reactant: [I-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Fc1cccnc1-c1nc(Cl)ccc1I
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 161.6 %

Procedure:
A 500 mL 3 neck RBF equipped with mechanical stirrer, reflux condenser, and addition funnel was charged with 6-chloro-3′-fluoro-[2,2′-bipyridin]-3-amine (6.63 g, 29.6 mmol). It was treated with 2M sulfuric acid (111 mL, 222 mmol) creating a yellow/orange solution. The reaction was cooled to −5° C. and treated dropwise with a solution of sodium nitrile (2.66 g, 38.5 mmol) in 49 mL water at −5° C. The yellow/orange suspension was stirred at 0° C. for 30 minutes, then treated dropwise with a solution of potassium iodide (14.76 g, 89 mmol) in 63 mL of water. The reaction was stirred at room temperature for 30 minutes, then heated to 80° C. for 1 hour. After cooling, the reaction was extracted with EtOAc, washed with water, 2M Na2CO3, NaHSO3, and brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography using 20% EtOAc/hexanes to give 6-chloro-3′-fluoro-3-iodo-2,2′-bipyridine (16 g, 81% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][NH2:10])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH:11]1([NH:14][C:15]2[N:20]3[N:21]=[CH:22][C:23](/[CH:24]=[C:25]4/[C:26](=[O:31])[NH:27][C:28](=[O:30])[NH:29]/4)=[C:19]3[N:18]=[C:17](S(C)(=O)=O)[N:16]=2)[CH2:13][CH2:12]1.C1(NC2N3N=CC(/C=C4/C(=O)NC(=O)N/4)=C3N=C(S(C)=O)N=2)CC1>CN1C(=O)CCC1>[CH:11]1([NH:14][C:15]2[N:20]3[N:21]=[CH:22][C:23](/[CH:24]=[C:25]4/[C:26](=[O:31])[NH:27][C:28](=[O:30])[NH:29]/4)=[C:19]3[N:18]=[C:17]([NH:10][CH2:9][C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)[N:16]=2)[CH2:12][CH2:13]1
Reactant: CS(=O)(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Reactant: Cc1ccc(CN)cc1C
Agent: CS(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Solvent: CN1CCCC1=O
Product: Cc1ccc(CNc2nc(NC3CC3)n3ncc(/C=C4\NC(=O)NC4=O)c3n2)cc1C
Temperature: 80 °C

Procedure:
A solution of (3,4-dimethylphenyl)methanamine in NMP (106 μl, 0.4 M, 1.5 eq, 0.042 mmol) was transferred in a glass reaction vial. A solution of a (1:1) mixture of (Z)-5-((4-(cyclopropylamino)-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione and (Z)-5-((4-(cyclopropylamino)-2-(methylsulfinyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione in NMP (100 μl, 0.282M, 1.0 eq, 0.0282 mmol) was added. The mixture was heated at 80° C. for 5 hours. NMP was added (0.7 ml) and the solution subjected to preparative HPLC purification. Genevac evaporation provided (Z)-5-((4-(cyclopropylamino)-2-(3,4-dimethylbenzylamino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione as a solid (5.8 mg). LCMS (ES): >85% pure, m/z 419 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH:9]2[CH3:12])=[CH:4][CH:3]=1.C[Sn](C)(C)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[CH3:12][CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:11]=2)[CH2:6][CH2:7][NH:8]1
Reactant: C[Sn](C)(C)c1ccccn1
Reactant: CC1NCCc2ccc(Br)cc21
Product: CC1NCCc2ccc(-c3ccccn3)cc21

Procedure:
In close analogy to the procedure described above, 7-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with 2-trimethylstannyl-pyridine to provide the title compound.