Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[CH:7]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:22])[CH3:21])=[CH:15][CH:14]=1)#[CH:12].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[Cl:1][C:2]1[CH:7]=[C:6]([C:12]#[C:11][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:22])[CH3:21])=[CH:15][CH:14]=2)[CH:5]=[N:4][C:3]=1[C:9]#[N:10]
Reactant: C#Cc1ccc(NC(C)=O)cc1
Reactant: N#Cc1ncc(Cl)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C#Cc2cnc(C#N)c(Cl)c2)cc1
Temperature: 25 °C

Procedure:
A solution of 3,5-dichloropicolinonitrile (1.0 eq.), N-(4-ethynylphenyl)acetamide (from the previous step) (1.0 eq.), bis(triphenyl-phosphine)palladium chloride (10 mol %), copper iodide (10 mol %), and triethylamine (5.0 eq.) in DMF (0.04 M) was stirred at 60° C. for 4 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and water. The two phases were separated. The organic layer was washed twice with water, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give N-(4-((5-chloro-6-cyanopyridin-3-yl)ethynyl)phenyl)acetamide as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[C:9]([SH:13])[CH:10]=[CH:11][CH:12]=1.[F:14][C:15]1[C:20](F)=[CH:19][C:18]([CH2:22][OH:23])=[C:17]([N+:24]([O-:26])=[O:25])[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[C:9]([S:13][C:20]2[C:15]([F:14])=[CH:16][C:17]([N+:24]([O-:26])=[O:25])=[C:18]([CH2:22][OH:23])[CH:19]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1CO
Reactant: Sc1cccc(C2OCCCO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(F)c(Sc2cccc(C3OCCCO3)c2)cc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[1,3]Dioxan-2-yl-benzenethiol (2.57 g, 14.02 mmol), prepared as described in Example 1, Step C, (4,5-difluoro-2-nitro-phenyl)-methanol (2.65 g, 14.02 mmol), and cesium carbonate (9.1 g, 28 mmol) were combined in DMF (100 mL). The resulting mixture was stirred overnight at room temperature. Water was added, and the resulting mixture was then extracted with ethyl acetate. The organic layer was dried with Na2SO4 and filtered, and the solvent was removed to yield an oil, which was purified via silica column chromatography (50% EtOAc/heptane) to yield a solid.
Reaction SMILES: [C:1](/[C:3](/[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1)=[CH:4]\[C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17](=[O:23])[CH2:18][CH2:19][C:20]([O-])=[O:21])[CH2:12][CH2:11]2)=[CH:7][CH:6]=1)#[N:2].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[CH2:52]([N:54]([CH2:62][CH3:63])[C:55]1[CH:60]=[CH:59][C:58]([NH2:61])=[CH:57][CH:56]=1)[CH3:53]>C(Cl)Cl>[CH2:62]([N:54]([CH2:52][CH3:53])[C:55]1[CH:60]=[CH:59][C:58]([NH:61][C:20](=[O:21])[CH2:19][CH2:18][C:17]([O:16][CH:13]2[CH2:14][CH2:15][N:10]([C:8]3[S:9][C:5](/[CH:4]=[C:3](\[C:1]#[N:2])/[C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=4)=[CH:6][CH:7]=3)[CH2:11][CH2:12]2)=[O:23])=[CH:57][CH:56]=1)[CH3:63]
Reactant: COc1ccc(/C(C#N)=C/c2ccc(N3CCC(OC(=O)CCC(=O)[O-])CC3)s2)cc1OC
Reactant: CCN(CC)c1ccc(N)cc1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCN(CC)c1ccc(NC(=O)CCC(=O)OC2CCN(c3ccc(/C=C(\C#N)c4ccc(OC)c(OC)c4)s3)CC2)cc1
Reaction time: 0.5 h
Yield: 49 %

Procedure:
Compound 18 (500 mg) was dissolved in methylene chloride (10 mL), and 2-chloro-4,6-dimethoxy-1,3,5-triazine (224 mg) and N-methylmorpholine (129 μL) were added to the solution, followed by stirring with ice cooling for 30 minutes. Subsequently, N,N-diethyl-1,4-phenylenediamine (209 μL) and N methylmorpholine (215 μL) were added to the mixture, followed by stirring at room temperature for 17 hours. The solvent was evaporated to dryness, and the residue was purified by silica gel column chromatography (CHCl3-MeOH), to thereby yield the target product (yield: 322 mg, 49%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH3:19])[CH:12]=[CH:11][C:10]=1[C:20]([CH3:23])(O)[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>O1CCCC1.Cl>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH3:19])[CH:12]=[CH:11][C:10]=1[C:20]([CH3:23])=[CH2:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc2ccc(C(C)(C)O)c(OCc3ccccc3)c12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)c1ccc2cccc(C)c2c1OCc1ccccc1
Yield: 59 %

Procedure:
1.8 g of 1-(1-benzyloxy-8-methyl-2-naphthyl)-1-methyl-1-ethanol was dissolved in 20 ml of tetrahydrofuran, to which 30 ml of 3N hydrochloric acid was added, followed by refluxing for 2 hours. The reaction solution was returned to room temperature, to which water was added, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated saline solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (4% ethyl acetate/hexane) to obtain 1.0 g of the captioned compound as a yellowish green oily substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([OH:11])[CH:5]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:6]([O:11][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(O)c1
Reactant: CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1OCCCCCCCCCCCCCC
Yield: 29.7 %

Procedure:
A mixture of 1.0 g (6.6 mmol) of 3,4-dihydroxybenzoic acid methyl ester, 4.1 ml (14 mmol) of 1-bromotetradecane and 2.5 g (17.9 mmol) of potassium carbonate in 50 ml of DMF was stirred and heated at 100° for 65 hours. The solvent was removed using high vacuum, water was added to the residue and the product was extracted with ethyl acetate. The dried extract was concentrated to a solid which was recrystallized from methanol-water to give 1.1 g (30% yield, mp 49°-50°) of 3,4-bis(tetradecyloxy)benzoic acid methyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][CH2:11][C@H:12]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([F:27])[CH:21]=1)[CH3:9].[CH2:36]([Sn](CCCC)(CCCC)C=C)[CH2:37]CC>O1CCOCC1>[Si:29]([O:28][C@@H:12]([CH2:11][O:10][C@@H:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:36]=[CH2:37])[CH3:9])[CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([F:27])[CH:21]=1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: Cc1ccc(C[C@@H]2CCCN2C[C@H](CO[C@H](C)c2ccccc2Br)O[Si](C)(C)C(C)(C)C)cc1F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: C1COCCO1
Product: C=Cc1ccccc1[C@@H](C)OC[C@@H](CN1CCC[C@H]1Cc1ccc(C)c(F)c1)O[Si](C)(C)C(C)(C)C
Temperature: 100 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
(2S)-1-[(2R)-3-[(1R)-1-(2-Bromophenyl)ethoxy]-2-{[tert-butyl(dimethyl)silyl]oxy}propyl]-2-(3-fluoro-4-methylbenzyl)pyrrolidine (1712 mg, 3.03 mmol), which had been obtained in Example 180 (180b), was dissolved in 1,4-dioxane (30 mL), added with tributyl(vinyl) tin (1.33 mL, 4.55 mL) and tetrakistriphenyl phosphine palladium (347 mg, 0.30 mmol), and stirred for 16 hours at 100° C. After cooling the reaction solution to room temperature, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=4/1) and basic silica gel column chromatography (n-hexane/ethyl acetate=4/1) to give the title compound as a colorless oily substance (1210 mg, yield 78%).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([I:16])=[CH:9][CH:10]=3)[C@:5]3([CH2:21][O:20][CH2:19][C:18](=O)[NH:17]3)[C:4]=2[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([I:16])=[CH:9][CH:10]=3)[C@:5]3([CH2:21][O:20][CH2:19][C:18](=[S:32])[NH:17]3)[C:4]=2[CH:3]=1
Reactant: O=C1COC[C@]2(N1)c1cc(Br)ccc1Oc1ccc(I)cc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: S=C1COC[C@]2(N1)c1cc(Br)ccc1Oc1ccc(I)cc12
Reaction time: 7 h
Yield: 130.4 %

Procedure:
In a 250-mL flask, the (S)-2′-bromo-7′-iodospiro[morpholine-3,9′-xanthen]-5-one (1.483 g, 3.14 mmol) was suspended in toluene (30 mL). Lawesson's reagent (0.794 g, 1.963 mmol) was added. An air-cooled condenser was affixed, and the reaction vessel was placed in a 90° C. oil bath. After 7 h, the reaction was concentrated. Without working it up, the residue was purified by chromatography (15% EtOAc/hexanes) to afford (S)-2′-bromo-7′-iodospiro[morpholine-3,9′-xanthene]-5-thione (1.25 g, 2.56 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2N=CC=N2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[NH:16]1[CH:20]=[CH:19]N=[CH:17]1>>[N:11]1([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=2[C:7]([OH:9])=[O:8])[CH:19]=[CH:20][N:16]=[CH:17]1
Reactant: c1c[nH]cn1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Product: Cc1ccc(-n2ccnc2)c(C(=O)O)c1

Procedure:
The title compound was synthesized following the same general protocol as described for 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A11, using imidazole. ESI-MS (m/z): 203 [M+1]+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].CCN(C(C)C)C(C)C.Cl.[CH3:18][NH:19][O:20][CH3:21]>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([N:19]([O:20][CH3:21])[CH3:18])=[O:6]
Reactant: O=C(Cl)CCCBr
Reactant: CNOC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)CCCBr
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Bromobutanoyl chloride (5.62 ml, 48.5 mmol) in DCM (64 ml) was added slowly to a solution of DIPEA (17.80 ml, 102 mmol) and N,O-dimethylhydroxylamine hydrochloride (4.97 g, 51.0 mmol) in DCM (32 ml) at 0° C. The mixture was stirred at room temperature for 16 hours then diluted with DCM (50 ml). The mixture was washed with 1M HCl(aq) (2×50 ml) and saturated NaHCO3(aq) (2×50 ml). The organic phase was passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 30% EtOAc/hexane afforded the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([CH3:12])=[CH:10][S:11][C:5]=2[N:4]=[C:3]1[SH:13].[OH-].[Na+].O.CN(C=O)C.[C:22]([O:25][C:26]1[CH:41]=[CH:40][C:29]([C:30]([C:32]2[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=2)=[O:31])=[CH:28][CH:27]=1)(=[O:24])[CH3:23]>C(O)C.O>[C:22]([O:25][C:26]1[CH:41]=[CH:40][C:29]([C:30]([C:32]2[CH:33]=[CH:34][C:35]([CH2:36][S:13][C:3]3[N:2]([CH3:1])[C:7](=[O:8])[C:6]4[C:9]([CH3:12])=[CH:10][S:11][C:5]=4[N:4]=3)=[CH:38][CH:39]=2)=[O:31])=[CH:28][CH:27]=1)(=[O:24])[CH3:23]
Reactant: Cc1csc2nc(S)n(C)c(=O)c12
Reactant: CC(=O)Oc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(=O)Oc1ccc(C(=O)c2ccc(CSc3nc4scc(C)c4c(=O)n3C)cc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
To a solution of 3,5-dimethyl-2-mercaptothieno[2,3-d]pyrimidin-4(3H)-one (1.40 g) and 1N-sodium hydroxide/water (6.7 ml) in ethanol (13 ml)-DMF (25 ml) was added 4-(4-acetoxybenzoyl)benzyl bromide (2.68 g) and the mixture was stirred at room temperature at 60° C. for 1 hour. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated, and the residue was recrystallized from methanol to provide the title compound as colorless solid (887 mg).
Reaction SMILES: [S:1]([C:5]1[CH:14]=[CH:13][C:12]([NH:15][N:16]=[C:17]([C:20]([CH3:22])=[O:21])[C:18]#[N:19])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)(O)(=[O:3])=[O:2].[K].P(Cl)(Cl)([Cl:26])=O>CN1CCCC1=O>[Cl:26][S:1]([C:5]1[CH:14]=[CH:13][C:12]([NH:15][N:16]=[C:17]([C:20]([CH3:22])=[O:21])[C:18]#[N:19])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)(=[O:3])=[O:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)C(C#N)=NNc1ccc(S(=O)(=O)O)c2cccnc12
Agent: [K]
Solvent: CN1CCCC1=O
Product: CC(=O)C(C#N)=NNc1ccc(S(=O)(=O)Cl)c2cccnc12
Reaction time: 1 h

Procedure:
To a 250 ml round-bottom flask fitted with calcium sulfate drying tube was added 4.5 g (0.0126 m) of 2-(5-sulfo-8-quinolylhydrazono)acetoacetonitrile, potassium salt and 45 ml phosphorus oxychloride. The resultant slurry was chilled to <5° C. and 4.5 ml N-methylpyrrolidinone was slowly added. After stirring 1 hour. at 0°-5° C., the slurry was stirred overnight at room temperature followed by quenching in 500 ml ice water. The resultant yellow solid was collected, air dried and recrystallized from 100 ml acetonitrile. Yield 3.0 g yellow needles (70 percent).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[NH2:46][C:47]([CH:51]1[CH2:53][CH2:52]1)([CH3:50])[C:48]#[N:49]>C(OC(=O)C)C.CN(C=O)C>[CH3:50][C:47]([NH:46][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:2]([Br:1])=[CH:7][N:6]=1)=[O:10])([C:48]#[N:49])[CH:51]1[CH2:53][CH2:52]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(Br)cn1
Reactant: CC(N)(C#N)C1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C#N)(NC(=O)c1cc(OCC(F)(F)F)c(Br)cn1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
To a solution of 5-Bromo-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 78d, 1.0 g, 3.33 mmol) dry DMF (15 ml) were added TBTU (1.12 g, 3.5 mmol) and triethylamine (675 mg, 929 μl, 6.67 mmol). The reaction mixture was stirred at room temperature for 30 minutes followed by addition of 2-amino-2-cyclopropylpropanenitrile (CAN 37024-73-0, 404 mg, 3.67 mmol). The reaction was stirred at room temperature for 18 hours. The reaction mixture was poured into a separatory funnel, diluted with ethylacetate and extracted with an 1.0M aqueous solution of sodium bicarbonate. The organic phase was collected and the aqueous phase was back-extracted with ethylacetate. The organic phases were combined, dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting a heptane/ethylacetate gradient to yield the title compound (910 mg, 70%) as a light yellow oil. MS (ESI, m/z): 392.3 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH:5]=1.[ClH:17]>>[ClH:17].[CH2:12]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH3:11])[N:7]=1)[C:3]([OH:16])=[O:2])[CH:13]([CH3:15])[CH3:14]
Reactant: COC(=O)c1cc(CC(C)C)nc(OC)c1
Agent: Cl
Product: COc1cc(C(=O)O)cc(CC(C)C)n1

Procedure:
A solution of 2-isobutyl-6-methoxy-isonicotinic acid methyl ester (1.20 g, 5.38 mmol) in 25% aq. HCl (60 mL) is stirred at 65° C. for 16 h. The solvent is removed in vacuo and the residue is dried under HV to give 2-isobutyl-6-methoxy-isonicotinic acid hydrochloride (1.20 g) as a solid; LC-MS*: tR=0.48 min, [M+1]+=210.1.
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].CN(C)C=O.[Cl:12][C:13]1[CH:14]=[C:15]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:29]=[CH:30][CH:31]=[C:32]4[C:36]=3[N:35]([CH3:37])[CH:34]=[CH:33]4)[N:24]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH:20]([CH3:22])[CH3:21]>ClCCl>[Cl:12][C:13]1[CH:14]=[C:15]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:29]=[CH:30][CH:31]=[C:32]4[C:36]=3[N:35]([CH3:37])[CH:34]=[C:33]4[CH:2]=[O:3])[N:24]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH:20]([CH3:21])[CH3:22]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4ccn(C)c34)no2)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C=O)cn(C)c34)no2)cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of oxalyl chloride (2.1 mL) in dichloromethane (125 mL) at 0° C. was added a solution of N,N-dimethylformamide (2.32 mL) in Dichloromethane (DCM) (75 mL) dropwise during 30 mins. The reaction mixture was stirred at 0° C. for another 15 minutes. A solution of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indole (D58) (7.4 g) in Dichloromethane (100 mL) was added in one portion. the mixture was stirred and warmed to room temperature slowly. After stirred at room temperature for 5 hours, dichloromethane was evaporated off. Ethyl acetate (300 mL), water (100 mL) and concentrated HCl solution (5 mL) was added to the residue. The mixture was stirred for 30 minutes and KOH was added to adjust pH value to about 8. The organic layer was separated, washed with water and brine, then dried over MgSO4. Filtration and evaporation afforded the product 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indole-3-carbaldehyde (D61) (5.2 g). δH (CDCl3, 400 MHz): 1.47 (6H, d), 3.87 (3H, s), 4.71-4.77 (1H, m), 7.09 (1H, d), 7.44 (1H, t), 7.68 (1H, dd), 7.72 (1H, s), 7.89 (1H, dd), 8.26 (1H, d), 8.56 (1H, dd), 10.06 (1H, s). MS (ES): C21H18ClN3O3 requires 395. found 396.1 (M+H+).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]1([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>S(=O)(=O)(O)O>[CH:5]1([C:11]2[CH:12]=[CH:13][C:14]([C:17](=[O:19])[CH3:18])=[CH:15][C:16]=2[N+:1]([O-:4])=[O:2])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1ccc(C2CCCCC2)cc1
Agent: O=S(=O)(O)O
Product: CC(=O)c1ccc(C2CCCCC2)c([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
A mixture of concentrated sulfuric acid & nitric acid (68-72%) (1.7:6, 15 mL) is added drop wise to a cold solution of 1-(4-cyclohexylphenyl)ethanone (6 g, 0.03 mol) in concentrated sulfuric acid (15 mL) at 0-5° C. Reaction mixture is allowed to stir at this temperature for 30 minutes & is then poured into crushed ice. It is then extracted with ethyl acetate (3×40 mL). Combined organic layer is dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography (silica gel, 230-400 mesh, ethyl acetate:n-hexane 1:9) to yield 1-(4-cyclohexyl-3-nitrophenyl)ethanone.
Reaction SMILES: [CH2:1]([C:5]1[CH:27]=[CH:26][C:8]([CH2:9][N:10]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>CO>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:26][CH:27]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(CN(CCCCCCC(=O)OCC)S(C)(=O)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1ccc(CN(CCCCCCC(=O)O)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 101.4 %

Procedure:
To a solution of the title compound of Step A (379 mg, 0.95 mmol) in MeOH (6 mL) was added NaOH (1.0 mL, 5N). The reaction was stirred at room temperature for 24 h and was acidified with aqueous HCl (1N). The MeOH was removed in vacuo and the residue was dissolved in CH2Cl2. The organic solution was washed sequentially with HCl (1N, 1×), water (2×), and brine (1×). The organic solution was dried with MgSO4, filtered, and concentrated in vacuo. Purification by radial chromatography (CH2Cl2 to 6% MeOH/CH2Cl2) provided the title compound (356 mg). 1H NMR (400 MHz, CDCl3) δ7.30-7.12 (m, 4H), 4.35 (s, 2H), 3.10-3.19 (m, 2H), 2.80 (s, 3H), 2.60 (t, 2H), 2.31 (t, 2H), 1.48-1.65 (m, 7H), 1.20-1.40 (m, 6H). 0.97 (t, 3H); MS 387 (M+18).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[OH:10][C:11]1[CH:18]=[C:17]([CH3:19])[C:14]([C:15]#[N:16])=[C:13]([CH3:20])[N:12]=1.[OH-].[Na+]>O>[OH:10][C:11]1[C:18]([N+:1]([O-:4])=[O:2])=[C:17]([CH3:19])[C:14]([C:15]#[N:16])=[C:13]([CH3:20])[N:12]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(O)nc(C)c1C#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(O)c([N+](=O)[O-])c(C)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
To a stirring mixture of nitric acid (fuming, 36 mL) and sulfuric acid (18 mL) was added 6-hydroxy-2,4-dimethylnicotinonitrile (step 1, 9.0 g, 60.8 mmol) in one portion, and the mixture was stirred at room temperature. After 1 h, the mixture was poured in water (100 mL) and neutralized with 2N aqueous NaOH. The resulting precipitates were collected by filtration to afford 3.2 g (27%) of the title compound: 1H-NMR (DMSO-d6) δ 2.28 (3H, s), 2.11 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[N:7][C:6]=2[N:20]=1.[CH3:29][N:30]([CH:32](OC)OC)[CH3:31]>CN(C=O)C>[Cl:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([Cl:27])[C:21]=1[C:3]1[C:2]([N:1]=[CH:29][N:30]([CH3:32])[CH3:31])=[N:20][C:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[N:9]=[CH:10][C:5]=2[CH:4]=1
Reactant: COC(OC)N(C)C
Reactant: CCN(CC)CCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N=CN(C)C)nc2n1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 68 %

Procedure:
To a suspension of 210 mg (1 mmol) of 7-amino-6-(2,6-dichlorophenyl)-2-[3-(diethylamino)propylamino]-pyrido[2,3-d]pyrimidine from Example 20 in 0.8 mL of DMF was added 0.8 mL of DMF dimethyl acetal. The mixture was stirred at room temperature for 5.5 hours, then concentrated in vacuo. The residual oil was distributed between dichloromethane and water. The organic phase was dried over magnesium sulfate, then concentrated to a glass that was crystallized from acetonitrile to give 160 mg (68%) of N'-[6-(2,6-dichlorophenyl)-2-{3-(diethylamino)propylamino}-pyrido[2,3-d]pyrimidin-7-yl]-N,N-dimethylformamidine, mp 100-104° C. CIMS (1% ammonia in methane): m/z (relative intensity) 476 (MH+ +2, 60), 474 (MH+, 94), 361 (100).
Reaction SMILES: [N+:1]([CH:4]1[CH:19]([OH:20])[CH:8]2[O:9][CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:11][CH2:12][CH:7]2[CH2:6][CH:5]1[OH:21])([O-])=O>CO.[NH4+].[OH-].[Ni]>[NH2:1][CH:4]1[CH:19]([OH:20])[CH:8]2[O:9][CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:11][CH2:12][CH:7]2[CH2:6][CH:5]1[OH:21]
Reactant: O=[N+]([O-])C1C(O)CC2COC(c3ccccc3)OC2C1O
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NC1C(O)CC2COC(c3ccccc3)OC2C1O
Reaction time: 20 h
Yield: 80.7 %

Procedure:
To a solution of rac-(2R,4aR,6R,7S,8R,8aR)-7-nitro-2-phenylhexahydro-4H-benzo[d][1,3]dioxine-6,8-diol (Carb. Res. 2002, 337, 1979-1992) (900 mg, 3.05 mmol) in MeOH (25 mL) and NH4OH (28% aqueous solution, 0.4 mL) was added Raney-Nickel (˜3 g). The mixture was hydrogenated at room temperature under atmosphere pressure for 20 h. The catalyst was filtered off and washed with MeOH. Solvents were evaporated to give the crude product. This was purified by silica gel chromatography, eluted with 15% MeOH in DCM and 83:14:3 DCM-MeOH-ammonia to give pure rac-(2R,4aR,6R,7S,8R,8aR)-7-amino-2-phenylhexahydro-4H-benzo[d][1,3]dioxine-6,8-diol (653 mg, 81%) as a white solid. 1H NMR (600 MHz, CD3OD) δ 7.52-7.50 (m, 2H), 7.37-7.32 (m, 3H), 5.58 (s, 1H), 4.13 (dd, J=11.0, 4.3, 1H), 3.68 (t, J=11.0, 1H), 3.51-3.41 (m, 3H), 2.67 (t, J=9.3, 1H), 1.83-1.76 (m, 2H), 1.17 (q, J=13.0, 1H).