Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([P+:3]([CH2:8]O)([CH2:6]O)[CH2:4]O)O.[Cl-:10].[CH3:11][NH:12][C:13]([NH:15][CH3:16])=[O:14]>C1(C)C=CC=CC=1>[Cl-:10].[CH3:11][N:12]([CH2:8][P+:3]1([CH2:1][N:12]([CH3:11])[C:13]([NH:15][CH3:16])=[O:14])[CH2:4][N:15]([CH3:16])[C:13](=[O:14])[N:12]([CH3:11])[CH2:6]1)[C:13]([NH:15][CH3:16])=[O:14]
Reactant: CNC(=O)NC
Reactant: OC[P+](CO)(CO)CO
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CNC(=O)N(C)C[P+]1(CN(C)C(=O)NC)CN(C)C(=O)N(C)C1
Yield: 67.5 %

Procedure:
Reaction of THPC (19.06 g, 0.1 mol) with 1,3-dimethylurea (26.44 g, 0.3 mol) in toluene (75 ml), following Example 19, gave 25.85 g (67.5%) of 5,5-bis(1,3-dimethylureidomethyl)-1,3-dimethyl-2-oxo-1,3-diaza-5-phosphoniacyclohexane chloride (IV, R=R'=CH3, X=Cl) as a white, crystalline solid, mp 191°-192.5° C. dec. The remainder (11.89 g) was a viscous yellow oil. Two recrystallizations from 2-propanol (5 ml/g), followed by thorough drying in a vacuum at 100° C., gave pure product, mp 196°-197° C. dec.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:21]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[S:20][CH:11](SCC2C=CC=CC=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si]([N:35]1[C:40](=[O:41])[C:39]([CH3:42])=[CH:38][N:37]([Si](C)(C)C)[C:36]1=[O:47])(C)(C)C>C(=O)([O-])[O-].[Cd+2].C1(C)C=CC=CC=1>[CH2:1]([O:8][C@@H:9]1[C@@H:21]([CH2:22][O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[S:20][C@@H:11]([N:37]2[CH:38]=[C:39]([CH3:42])[C:40](=[O:41])[NH:35][C:36]2=[O:47])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COC[C@H]2SC(SCc3ccccc3)C[C@@H]2OCc2ccccc2)cc1
Reactant: Cc1cn([Si](C)(C)C)c(=O)n([Si](C)(C)C)c1=O
Agent: O=C([O-])[O-]
Agent: [Cd+2]
Solvent: Cc1ccccc1
Product: Cc1cn([C@H]2C[C@H](OCc3ccccc3)[C@@H](COCc3ccccc3)S2)c(=O)[nH]c1=O
Reaction time: 0.5 h

Procedure:
A suspension of benzyl 3,5-di-O-benzyl-2-deoxy-1,4-dithio-D-erythro-pentofuranoside (22.5 g, 51.6 mmol), bis TMS-thymine (46 g, 170 mmol), mercuric bromide (20.5 g, 56.7 mmol), cadmium carbonate (29.3 g, 170 mmol) and dry toluene (1 L) was boiled under reflux, with stiring, for 24 hours. The hot mixture was then filtered and the solids were washed with toluene. The filtrate was successively washed with potassium iodide solution (30%) and water and then evaporated. The residue was taken up in 4:1 methanol-water, stirred for 30 minutes, the suspension filtered and the filtrate evaporated. The residue was applied to a silica gel column (hexane-ethyl acetate (1:1)) and combination of the appropriate fractions gave the title product as a clear colourless syrup. 1H NMR indicated the ratio of α- to β- anomers to be 2.8:1. Further column chromatography gave more of the separated anomers. The first compound to be eluted from the column was 3',5'-di-O-benzyl-4'-thio-thymidine as a colourless syrup. This could be crystallised from methanol to give colourless crystals m.p. 140°-142° C.
Reaction SMILES: [NH2:1][C:2](=[N:33][OH:34])[C:3]1[CH:4]=[C:5]2[C:22](=[CH:23][CH:24]=1)[O:21][C:8]1([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[CH2:7][CH:6]2[O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].N1C=CC=CC=1.Cl[C:42]([O:44][CH2:45][CH:46]([CH2:51][CH3:52])[CH2:47][CH2:48][CH2:49][CH3:50])=[O:43]>CN(C=O)C>[NH2:1][C:2](=[N:33][O:34][C:42]([O:44][CH2:45][CH:46]([CH2:51][CH3:52])[CH2:47][CH2:48][CH2:49][CH3:50])=[O:43])[C:3]1[CH:4]=[C:5]2[C:22](=[CH:23][CH:24]=1)[O:21][C:8]1([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[CH2:7][CH:6]2[O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O[Si](C)(C)C(C)(C)C)c1cc(C(N)=NO)ccc1O2
Reactant: CCCCC(CC)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCCCC(CC)COC(=O)ON=C(N)c1ccc2c(c1)C(O[Si](C)(C)C(C)(C)C)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 6-[amino(hydroxyimino)methyl]-4-{[tert-butyl(dimethyl)silyl]oxy}-spiro[chroman-2,4′-piperidine]-1′-carboxylate in 80 mL of DMF were added 3.78 mL of pyridine and 8.4 mL of 2-Ethylhexyl chloroformate at 0° C., and the reaction mixture was stirred at 0° C. for 1.5 h. The reaction mixture was poured into ice-cold brine, and extracted with AcOEt twice. The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in reduced pressure to give a crude product, which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].Br[C:13]1[CH:18]=[C:17]([F:19])[C:16]([OH:20])=[C:15]([Cl:21])[CH:14]=1>>[Cl:21][C:15]1[CH:14]=[C:13]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:18]=[C:17]([F:19])[C:16]=1[OH:20]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Oc1c(F)cc(Br)cc1Cl
Product: N#Cc1ccc(-c2cc(F)c(O)c(Cl)c2)cc1
Yield: 48 %

Procedure:
4-Cyanophenylboronic acid and 4-bromo-2-chloro-6-fluorophenol were processed as described in Example 167A to provide the title compound (48% yield). 1HNMR (300 MHz, MeOD) δ7.40 (m, 1H), 7.52 (m, 1H), 7.78 (s, 4H); MS (CDI) m/z 248 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[CH3:9][O-:10].[Na+].CO>CO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:10][CH3:9])[N:3]=1
Reactant: C[O-]
Reactant: Brc1cccc(Br)n1
Agent: [Na+]
Solvent: CO
Product: COc1cccc(Br)n1
Reaction time: 2 h

Procedure:
While heating under stirring a mixture of 200 g of 2,6-dibromopyridine and 150 ml of methanol on an oil bath at 80° C., 250 ml of a 28% sodium methoxide/methanol solution was added dropwise slowly. The mixture was heated under stirring as it was for 2 hours, and after standing to cool, it was extracted with diethyl ether-water. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was removed, to give 150 g of the title compound.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[S:23](Cl)(=[O:25])=[O:24].C1COCC1.C(N(CC)CC)C>C(Cl)Cl>[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[S:23]([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])(=[O:24])=[O:25]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1OS(=O)(=O)c1ccc2ccccc2c1
Reaction time: 1 h

Procedure:
N-2-Naphthalenesulfonyloxyphthalimide was prepared by the following procedure. To a flask equipped with a stirrer and addition funnel were added N-hydroxyphthalimide (8.15 g, 0.050 mol), 2-naphthalenesulfonyl chloride (11.4 g, 0.050 mol) and 125 mL of THF. A solution of triethylamine (8 mL, 0.058 mol) and 25 mL of THF was added dropwise. After 1 h stirring, the reaction mixture was diluted with 200 mL of methylene chloride and the organic layer was washed successively with water, 3 percent aqueous sodium bicarbonate, and water. The organic layer containing crystallized product was evaporated leaving 16.8 g of an off-white solid. Recrystallization from toluene gave 12.33 g (69.8%) of white, crystalline N-2-naphthalenesulfonyloxyphthalimide: mp 223°-225°; nmr (CDCl3 -DMSO-d6) 8.8-7.7 (m), singlet at 7.9; uv (CH3CN) 220 (67,000), 234 (79,800), 279 (6880), 317 (1825), 331 nm (1950); ir (nujol) 1787 (m), 1737 (s), 1380 (m), 1190 (s), 965 (s); mass spectrum 353.0350 (calcd for C18H11NO5S: m+, 353.0357). Anal. Calcd for C18H11NO5S: C, 61.19; H, 3.14; N, 3.96; O, 22.64; S, 9.07. Found: C, 61.03, 61.01; H, 3.13, 3.35; N, 4.06, 3.98.
Reaction SMILES: [CH2:1]([C:8]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([C:8]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(Cc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(Cc2ccccc2)CCNCC1
Yield: 71.8 %

Procedure:
A solution of 1-tert-butyl 4-ethyl 4-benzylpiperidine-1,4-dicarboxylate (step 2, 4.5 g, 12.96 mmol) in DCM (50 ml) was cooled to 0° C. After ten minutes, trifluoroacetic acid (6.0 g) was added and stirred the reaction at room temperature for about 6 hours. After completion of the reaction (monitored by TLC), the reaction mixture was neutralized with sat. NaHCO3, extracted with DCM, dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (2.3 g) as a light yellow liquid. 1H NMR (300 MHz, CDCl3): 1.19-1.24 (t, 3H); 1.48-1.58 (m, 2H); 2.14-2.18 (m, 2H); 2.64-2.73 (m, 2H); 2.86 (s, 2H); 3.01-3.07 (m, 4H); 4.10-4.17 (m, 2H); 7.07-7.10 (m, 2H); 7.24-7.30 (m, 3H); ES Mass: 248 (100%) [M+1].
Reaction SMILES: OC1O[C@H](C)[C@H](O)C[C@H]1O.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)#[N:12].C([O-])([O-])=O.[K+].[K+].[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Br>CC(C)=O>[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]#[N:12])=[CH:14][CH:15]=1
Reactant: Fc1cccc(CBr)c1
Reactant: N#Cc1ccc(O)cc1
Agent: C[C@H]1OC(O)[C@H](O)C[C@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(OCc2cccc(F)c2)cc1
Yield: 87.2 %

Procedure:
(Nakamoto, Kazutaka; Tsukada, Itaru; Tanaka, Keigo; Matsukura, Masayuki; Haneda, Toru; Inoue, Satoshi; Ueda, Norihiro; Abe, Shinya; Hata, Katsura; Watanabe, Naoaki, WO 2005033079 (2005)). A mixture of 4-cyanophenol (11.91 g, 100.0 mmol), K2CO3 (55.20 g, 400.0 mmol), and 3-fluorobenzylbromide (22.68 g, 120.0 mmol) were heated in acetone (400 mL) at reflux (5 h). The volatiles were evaporated and the residue was diluted in CH2Cl2 (300 mL), and then washed with H2O (500 mL), dried (MgSO4), and concentrated in vacuo to give white needles (19.81 g, 87%): Rf=0.45 (hexanes/EtOAc 9/1); mp 104-105° C.; 1H NMR (CDCl3) δ 5.11 (s, CH2O), 6.98-7.20 (m, 5 ArH), 7.33-7.41 (m, 1 ArH), 7.59 (d, J=8.7 Hz, 2 ArH); HRMS (M+Na+) (ESI+) 250.0641 [M+Na+] (calcd for C14H10NONa+250.0641).
Reaction SMILES: [CH2:1]([CH:4]([CH:10]([CH3:12])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]=C.C[OH:14]>>[CH:10]([CH:4]([CH2:1][CH:2]=[O:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:12])[CH3:11]
Reactant: CO
Reactant: C=CCC(C(=O)OCC)C(C)C
Product: CCOC(=O)C(CC=O)C(C)C
Yield: 89 %

Procedure:
In 100 g of methanol were dissolved 10.0 g of ethyl α-allylisovalerate (general formula [XI] wherein R=--CH2CH3) and, under cooling at -20°~-10° C. and stirring, ozone gas was bubbled into the solution for 8 hours. Then, at room temperature, the reaction mixture was added to 100 g of dimethyl sulfide and the mixture was stirred at that temperature overnight. The reaction mixture was then distilled under reduced pressure to remove the low-boiling fraction and the residue was diluted with 50 g of diethyl ether. Following the addition of 4 g of anhydrous calcium chloride, hydrogen chloride gas was bubbled into the mixture at room temperature for 10 minutes. Then, 5 g of anhydrous potassium carbonate were added and the mixture was thoroughly stirred. The diethyl ether solution was taken, washed with water, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the low-boiling fraction. By the above procedure there were obtained 9.0 g of ethyl 2-isopropyl-3-formyl-propionate (general formula [XII] wherein R=--CH2CH3) yield: 89% based on ethyl α-allylisovalerate; the NMR spectrum of the aldehyde (60 MHz) δHMSCDCl3 : 9.74].
Reaction SMILES: Cl.CO.C(=O)([S:6][CH:7]([CH2:9][C:10](=[O:15])[CH:11]([CH3:14])[CH2:12][CH3:13])[CH3:8])C>O>[SH:6][CH:7]([CH2:9][C:10](=[O:15])[CH:11]([CH3:14])[CH2:12][CH3:13])[CH3:8]
Reactant: CCC(C)C(=O)CC(C)SC(C)=O
Agent: Cl
Solvent: CO
Solvent: O
Product: CCC(C)C(=O)CC(C)S
Temperature: 40 °C
Reaction time: 48 h
Yield: 75.3 %

Procedure:
A reaction flask was charged with HCl (1.25 M, 500 mL) in methanol (0.63 mol). S-(5-methyl-4-oxoheptan-2-yl) ethanethioate (127.0 g, 0.63 mol) (synthesized as above in EXAMPLE I) then added into the reaction flask in one portion. The reaction mixture was stirred at 40° C. for about 48 hours, then cooled down to room temperature, and transferred into a separatory funnel Water (250 mL) was added. The reaction mixture was then extracted twice with ethyl acetate (250 mL each time). The organic phases were combined, washed with water (250 mL) followed by brine (100 mL), and then dried with magnesium sulfate. Further distillation of the obtained crude product under a vacuum (at 57° C. with a pressure of 1.33 mmHg) provided 2-mercapto-5-methyl-heptan-4-one (76.0 g) (about 76% yield with a purity over 98% monitored with gas chromatography).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:22])[C@@H:9]([NH:14]C(OC(C)(C)C)=O)[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:2]=1.[ClH:23]>ClCCl.O1CCOCC1>[ClH:23].[ClH:23].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:22])[C@@H:9]([NH2:14])[C:10]([CH3:11])([CH3:12])[CH3:13])[CH:2]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)Nc1cccnc1)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)[C@H](N)C(=O)Nc1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To a solution of (2S)-2-tert-butoxycarbonylamino-3,3-dimethylbutanoic acid 3-pyridylamide (1.6 g, 5.21 mmol) in dichloromethane (10 mL) cooled at 0° C. is added 4 M HCl in dioxane (10 mL). The resulting solution is allowed to warm to 25° C. and is stirred for 3 h. The reaction mixture is concentrated and the solid is filtered to provide (2S)-2-amino-3,3-dimethylbutanoic acid 3-pyridylamide dihydrochloride (1.40 g, 94% yield) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[Cl:5][C:6]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:7]=1[NH2:8].O>C(Cl)Cl>[Cl:5][C:6]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:7]=1[NH:8][CH2:2][C:3]#[N:4]
Reactant: N#CCCl
Reactant: Nc1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: O
Product: N#CCNc1ccc(Cl)cc1Cl
Reaction time: 1 h

Procedure:
Chloroacetonitrile (40 ml) and 2,4-dichloroaniline (81.0 g) were heated with stirring in a 250 ml round-bottomed three-necked flask at 120°-125° C. for 1.0 hour and then for approximately 1 hour at 140°-145° C. The reaction mixture was cooled, diluted with CH2Cl2, and then placed in a separatory funnel and water added. Shaking the mixture resulted in crystal formation. The mixture was filtered and 39.2 g of 2,4-dichloroaniline hydrochloride removed. The CH2Cl2 layer was then separated from the filtrate and the CH2Cl2 layer treated with diatomaceous earth and activated charcoal and then filtered. The CH2Cl2 was then evaporated off, leaving a black viscous gum which on cooling with stirring solidified. Recrystallization from carbon tetrachloride gave 21.5 g of 2,4-dichloroanilinoacetonitrile.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:15]3[CH2:23][NH:22][CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:26]=[N:27][C:28]([O:33][CH3:34])=[C:29]([CH:32]=1)[C:30]#[N:31].C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O.CO.C(O)(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:15]3[CH2:23][N:22]([C:25]4[CH:26]=[N:27][C:28]([O:33][CH3:34])=[C:29]([C:30]#[N:31])[CH:32]=4)[CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ncc(Br)cc1C#N
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2ncnc3c2CNCC3)C1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(C)(C)O
Product: COc1ncc(N2CCc3ncnc(N[C@H]4CCN(C(=O)OC(C)(C)C)C4)c3C2)cc1C#N
Temperature: 110 °C
Reaction time: 18 h
Yield: 29.3 %

Procedure:
To a glass vial was added (S)-3-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 23) (566 mg, 1.77 mmol), 5-bromo-2-methoxynicotinonitrile (453 mg, 2.13 mmol), cesium carbonate (1155 mg, 3.54 mmol), tris(dibenzylideneacetone)dipalladium(0) (162 mg, 0.18 mmol), X-Phos (287 mg, 0.60 mmol) and anhydrous tert-butanol (5 mL). The vial was flushed with a stream of argon for 15 sec and capped. The mixture was heated with stirring for 18 h at 110° C. Allowed to cool and partitioned between CH2Cl2 (20 mL) and water (10 mL) and filtered the biphasic mixture through a celite pad. The organic layer was separated by filtering through a phase separation tube and concentrated in vacuo. Purified by flash column chromatography on silica gel with heptane/EtOAc, 100/0 to 0/100 then EtOAc/MeOH (90/10) to give (S)-3-[6-(5-cyano-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester as a brown gum (234 mg, 29% yield). LCMS: [M+H]+=452.1, Rt(4)=0.90 min.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:20](/B(O)O)=[CH:21]\[CH2:22][CH2:23][CH2:24][CH3:25].C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:41].Cl.Cl>CCOCC>[ClH:41].[ClH:41].[CH:20](/[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[CH:21]\[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCC/C=C/B(O)O
Reactant: Brc1cnc2ccc(NCCCN3CCCC3)nn12
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCOCC
Product: CCCC/C=C/c1cnc2ccc(NCCCN3CCCC3)nn12
Yield: 36 %

Procedure:
Prepared from the product of step A and (E)-1-hexeneboronic acid according to general procedure 2. The free-base was converted to the dihydrochloride salt with 2N HCl in Et2O to provide the title compound (59 mg, 36%) as a brown solid; 1H NMR (500 MHz, CD3OD) δ 7.97 (s, 1H), 7.92 (d, J=9.9 Hz, 1H), 7.23 (d, J=9.9 Hz, 1H), 6.87-6.85 (m, 1H), 6.72-6.69 (m, 1H), 3.70-3.66 (m, 2H), 3.56 (t, J=6.7 Hz, 2H), 3.37-3.34 (m, 2H), 3.13-3.08 (m, 2H), 2.37-2.33 (m, 2H), 2.22-2.13 (m, 4H), 2.06-2.02 (m, 2H), 1.56-1.50 (m, 2H), 1.47-1.41 (m, 2H), 0.97 (t, J=7.3 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 157.1, 139.2, 133.2, 130.4, 121.3, 120.7, 117.6, 114.2, 55.3, 54.2, 39.7, 34.3, 32.3, 26.0, 24.1, 23.3, 14.3; HPLC tR=12.3 min (Luna), 97.6%; ES-MS: (M+H)=328 m/z.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][C:9]([CH3:13])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[O:31])[CH:25]=[CH:26][C:27]=1[Cl:28].C([NH+](CC)CC)C>C1C=CC=CC=1>[C:1]1([N:7]2[C:11](=[O:12])[CH:10]([C:30](=[O:31])[NH:29][C:24]3[CH:25]=[CH:26][C:27]([Cl:28])=[C:22]([Cl:21])[CH:23]=3)[C:9]([CH3:13])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1=NN(c2ccccc2)C(=O)C1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: CC[NH+](CC)CC
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC1=NN(c2ccccc2)C(=O)C1C(=O)Nc1ccc(Cl)c(Cl)c1

Procedure:
The solution of 13 g of 1-phenyl-3-methyl-2-pyrazolin-5-one in 150 ml of benzene and 9.1 g of triethylamine is combined at ambient temperature with the solution of 14.0 g of 3,4-dichlorophenylisocyanate in the minimum amount of benzene. The triethylammonium salt separates after 2 hours standing at room temperature and the mixture is evaporated. The residue is poured into 0.3 N hydrochloric acid, the solid collected, washed with water, dried, triturated with cold methanol and recrystallized from ethyl acetate to yield the 1-phenyl-3-methyl-4-(3,4-dichlorophenylcarbamoyl)-2-pyrazolin-5-one of Formula II with R=H, R'=3--Cl and R"=Cl, melting at 228°-231° (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=O)[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]>S(Cl)(Cl)=O>[CH:4]1([NH:1][C:9](=[O:11])[C:8]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[OH:13])[CH2:12][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Solvent: O=S(Cl)Cl
Product: O=C(NC1CCCCC1)c1cc([N+](=O)[O-])ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 191.2 %

Procedure:
Thionyl chloride (20 ml) was added to 5-nitrosalicylic acid (5 g). The mixture was heated under reflux for 2 hr. Thionyl chloride was removed by distillation under the reduced pressure. Toluene was added to the residue, and the mixture was concentrated. This procedure was repeated twice. The residue was dissolved in methylene chloride (40 ml). Cyclohexylamine (9.4 ml) was added under ice cooling to the solution. The mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate. The diluted solution was washed with water, dilute hydrochloric acid, and water in that order, and then dried over magnesium sulfate. The solvent was then removed by distillation under the reduced pressure to give 6.9 g of N-cyclohexyl-5-nitrosalicylamide.
Reaction SMILES: [OH-].[K+].C([O:11][CH:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[N:15]([O:20][CH2:21][O:22][N:23]2[C:28]([CH3:30])([CH3:29])[CH2:27][CH:26]([O:31]C(=O)C3C=CC=CC=3)[CH2:25][C:24]2([CH3:41])[CH3:40])[C:14]([CH3:43])([CH3:42])[CH2:13]1)(=O)C1C=CC=CC=1>C(O)C>[OH:31][CH:26]1[CH2:27][C:28]([CH3:30])([CH3:29])[N:23]([O:22][CH2:21][O:20][N:15]2[C:14]([CH3:43])([CH3:42])[CH2:13][CH:12]([OH:11])[CH2:17][C:16]2([CH3:19])[CH3:18])[C:24]([CH3:41])([CH3:40])[CH2:25]1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OCON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC(O)CC(C)(C)N1OCON1C(C)(C)CC(O)CC1(C)C

Procedure:
The compound is prepared by the basic hydrolysis (potassium hydroxide in ethanol) of the compound prepared in Example 30A.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(N(CC)CC)C.[F:12][C:13]([F:47])([F:46])[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:17]=[C:16]([C:30]2[CH:31]=[C:32]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([S:42](Cl)(=[O:44])=[O:43])[CH:37]=3)[CH:33]=[CH:34][CH:35]=2)[N:15]=1>C1COCC1>[OH:2][CH2:1][CH2:3][NH:4][S:42]([C:38]1[CH:37]=[C:36]([C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([C:16]3[N:15]=[C:14]([C:13]([F:12])([F:46])[F:47])[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=4)[N:17]=3)[CH:31]=2)[CH:41]=[CH:40][CH:39]=1)(=[O:43])=[O:44]
Reactant: O=S(=O)(Cl)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Reactant: NCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCO)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Temperature: 0 °C
Yield: 67.8 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of ethanolamine (0.071 g, 1.16 mmol), triethylamine (0.06 ml, 0.42 mmol) and THF (2 ml) was added drop wise a solution of 3′-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-biphenyl-3-sulfonyl chloride (example I.3) (0.21 g, 0.39 mmol) in THF (3 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as a white solid (0.15 g, 69%). MS (ISP) 567.7 [(M+H)+]; mp 153° C.