Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:12]([CH2:20][CH3:21])=[N+:13]([O-])[CH:14]=[C:15]([CH2:17][CH3:18])[N:16]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:14]1[C:15]([CH2:17][CH3:18])=[N:16][C:11]([C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[O:2][CH3:1])=[C:12]([CH2:20][CH3:21])[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1c[n+]([O-])c(CC)c(-c2ccc(OC)cc2OC)n1
Product: CCc1nc(-c2ccc(OC)cc2OC)c(CC)nc1Cl
Temperature: 60 °C
Reaction time: 6 h

Procedure:
The product from step 2 (3.3 g) is dissolved in POCl3 (25 mL) and the resulting solution stirred at 60° C. for 6 hours. The reaction mixture is cooled, and the volatiles are removed under reduced pressure. Flash chromatography (1-4% ethyl acetate in hexanes) affords 2-chloro-5-(2,4-dimethoxy-phenyl)-3,6-diethyl-pyrazine as a clear oil. MS: 307. H-1 NMR (400 MHz, CDCl3): 1.16 (t, 3H), 1.31 (t, 3H), 2.60 (q, 2H), 3.00 (q, 2H), 3.75 (s, 3H), 3.76 (s, 3H), 6.53 (d, 1H), 6.59 (dd, 1H), 7.19 (d, 1H).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH2:7]([NH2:10])[CH:8]=[CH2:9]>O1CCCC1>[CH2:7]([NH:10][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH:8]=[CH2:9]
Reactant: C=CCN
Reactant: CCCC(=O)Cl
Solvent: C1CCOC1
Product: C=CCNC(=O)CCC
Temperature: 15 °C
Reaction time: 0.25 h
Yield: 101.6 %

Procedure:
Butyroyl chloride (194.7 g, 1.83 mol) in 1 L of tetrahydrofuran was added to a three neck round bottom flask equipped with a thermometer, stir bar, and dropping funnel. The contents of the flask were then cooled to 15° C. in an ice bath while stirring. Allylamine (208.7 g, 3.65 mol) in 50 mL of tetahydrofuran was then added slowly through the dropping funnel while maintaining stirring. Throughout the addition, the temperature was maintained at 15° C. . After addition was complete, stirring continued for an additional 15 minutes, after which the solid allylamine chloride precipitate was filtered off. The filtrate was concentrated under vacuum to yield 236.4 g of N-allyl butyramide as a colorless viscous liquid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:31]([CH2:35][CH2:36][OH:37])[CH2:32][CH2:33][OH:34]>C1COCC1>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([N:31]([CH2:35][CH2:36][OH:37])[CH2:32][CH2:33][OH:34])=[O:16])[CH2:6][CH2:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: OCCNCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)N(CCO)CCO)O2
Reaction time: 1.5 h
Yield: 9.3 %

Procedure:
To a solution of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (500 mg, 2.00 mmol) in 10 mL THF was added 356 mg CDI (2.20 mmol). After stirring for 1.5 h., a solution of diethanolamine (231 mg, 2.2 mmol) in 10 mL THF was added over 1 h and the reaction was stirred overnight. The reaction was concentrated, dissolved into 70 mL CH2Cl2 and washed sequentially with 50 mL 0.62 M HCl, 50 mL 1.0 M NaHCO3, 50 mL saturated NaCl and dried over Na2SO4. The combined aqueous phases were extracted 3×50 mL 3:1 isopropyl alcohol/isopropyl acetate which was dried and concentrated to a brown oil. Flash chromatography yielded 63 mg of 6-hydroxy-N,N-bis(2-hydroxyethyl)-2,5,7,8-tetramethylchroman-2-carboxamide as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[NH2:27][C:28]1[O:32][N:31]=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][C:28]2[O:32][N:31]=[CH:30][CH:29]=2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: Nc1ccno1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(Nc1ccno1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 5-aminoisoxazole via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(isoxazol-5-yl)terephthalamide. MS (Q1) 463 (M)+.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]([C:7]1[NH:8][N:9]=[CH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:6])[CH3:3].[CH2:17](I)[CH3:18]>C(O)C.C([O-])C.[Na+]>[CH2:2]([O:4][C:5]([C:7]1[N:8]([CH2:17][CH3:18])[N:9]=[CH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:6])[CH3:3]
Reactant: CCI
Reactant: CCOC(=O)c1cn[nH]c1C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cnn(CC)c1C(=O)OCC
Yield: 30.9 %

Procedure:
Sodium ethanolate solution was freshly prepared by dissolving sodium (240 mg) in ethanol (30 ml). 2H-Pyrazole-3,4-dicarboxylic acid diethyl ester (800 mg, 3.77 mmol) was dissolved in this sodium ethanolate solution (11 ml) and stirred for 10 min at RT, before ethyl iodide (1.4 g, 9 mmol) was added dropwise. After the completion of the addition, the mixture was heated to reflux until all starting material was consumed (1 h). The solvent was then evaporated, the residue was taken up in ethyl acetate and washed (water). The organic layer was dried (Na2SO4), evaporated, and the title compound (280 mg, 31%) was isolated from the mixture by column chromatography (silica gel, heptane:ethyl acetate=100:0-60:40). (The regioisomeric 1-ethyl-1H-pyrazole-3,4-dicarboxylic acid diethyl ester can also be isolated, and can be distinguished from the desired product by NOE-'H-NMR.)
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][N+:5]([O-:9])=[C:4]([CH3:10])[C:3]=1[CH3:11].[CH3:12][C:13]1([CH3:21])[O:18][CH2:17][CH:16]([CH2:19][OH:20])[CH2:15][O:14]1>C1(C)C=CC=CC=1>[CH3:12][C:13]1([CH3:21])[O:18][CH2:17][CH:16]([CH2:19][O:20][C:2]2[C:7]([CH3:8])=[CH:6][N+:5]([O-:9])=[C:4]([CH3:10])[C:3]=2[CH3:11])[CH2:15][O:14]1
Reactant: CC1(C)OCC(CO)CO1
Reactant: Cc1c[n+]([O-])c(C)c(C)c1Cl
Solvent: Cc1ccccc1
Product: Cc1c[n+]([O-])c(C)c(C)c1OCC1COC(C)(C)OC1
Reaction time: 2.5 h
Yield: 90.6 %

Procedure:
A mixture of 4-chloro-2,3,5-trimethylpyridine 1-oxide (840 g), (2,2-dimethyl-1,3-dioxan-5-yl)methanol (688 g) and toluene (2.52 L) was heated under reflux while removing a water content. While azeotropical dehydration was continued, potassium hydroxide (0.58 kg) was added to the reaction mixture over 3 hours and 45 minutes, and azeotropic dehydration was continued for 2.5 hours. The mixture was cooled to 30° C. or less, and ethyl acetate (2.5 L) and a 17% saline solution (3.5 L) were added to the mixture and then the mixture was allowed to stand for overnight. The ethyl acetate layer was separated and the aqueous layer was extracted with ethyl acetate (1.0 L×3). The ethyl acetate layers were combined, filtrated through celite, and concentrated under reduced pressure to obtain a desired product (1.20 kg).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:10]=1.I[CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH:23]1([CH2:22][CH:15]([C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCOC(=O)Cc1cccnc1
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(CC1CCCC1)c1cccnc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
LDA (50.1 mL of a 1.5 mmol mL-1 solution in c-C6H12, 7.6 mmol) was added to a stirred solution of ethyl 3-pyridylacetate (1.15 g, 6.9 mmol) in anhydrous THF-HMPA (3:1, 260 mL) at −78° C. After 30 min, iodomethylcyclopentane (1.46 g, 6.9 mmol) was added, then stirring was continued at −78° C. for 4.5 h. The mixture was allowed to warm to 20° C., before being stirred for 16 h. The reaction mixture was carefully quenched with saturated aqueous NH4Cl (20 mL), then H2O (100 mL) was added. The mixture was extracted with EtOAc (3×50 mL), then the extracts were dried (Na2SO4). Filtration, solvent evaporation, and column chromatography (n-C6H4-EtOAc) furnished ethyl 3-cyclopentyl-2-pyridin-3-ylpropionate: m/z (ES+)=248.3 [M+H]+. Step 2: A stirred solution of this compound (0.73 g, 3.0 mmol) in THF (3 mL) was treated with 2M NaOH (3 mL, 6.0 mmol). After 16 h at 20° C., the organic solvent was removed under reduced pressure, then the pH of the remaining solution was adjusted to 6.5, before being extracted with EtOAc. The EtOAc extracts were dried (Na2SO4), filtered, and concentrated to give the title compound: m/z (ES+)=220.2 [M+H]+. Preparation 3: (E)-3-Cyclopentyl-2-(6-methylsulfanylpyridin-3-yl)acrylic Acid
Reaction SMILES: C[O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30]C1C=CC=CC=1>C(O)C.[Pd]>[CH3:30][O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][OH:2]
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COCCOCCOCCOCCOCCOCCOCCOCCOCCO
Yield: 98.8 %

Procedure:
A solution of nonaethylene glycol benzyl methyl ether (10 g, 19.3 mmol) in ethanol (200 mL) was shaken with 10% palladium on activated charcal (Aldrich, 1.0 g) under hydrogen at 344.7 kPa (50 psi) on a Parr apparatus for 3 h. The catalyst was filtered off (Celite™), and the filtrate was concentrated in vacuo and dried by evaporation of toluene to provide nonaethylene glycol monomethyl ether as an oil (8.17 g, 99%), 1H-NMR (DMSO-d6) δ: 4.56 (t, 1 OH), 3.60-3.35 (m, 36, 18 OCH2),3.22 (s, 3, CH3).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:23](=O)[CH3:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([S:9]([NH:12][C@H:13]2[CH2:14][CH2:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]2)(=[O:10])=[O:11])=[CH:3][C:2]=1[NH:1][CH2:23][CH3:24]
Reactant: COC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(Cl)c(N)c2)CC1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CCNc1cc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)OC)CC2)ccc1Cl
Reaction time: 8 h

Procedure:
A round bottom flask was charged with methyl trans-4-(3-amino-4-chlorophenylsulfonamido)cyclohexamecarboxylate (Intermediate 10, 333 mg, 0.922 mmol) and acetaldehyde (52.1 μl, 0.922 mmol) followed by sodium triacetoxyborohydride (293 mg, 1.383 mmol) in DCE (9217 μl) and the reaction was stirred overnight. The reaction was diluted with DCM/sat'd NaHCO3, and the organic layer was separated and dried over MgSO4, then filtered and chromatographed on a Biotage 25S column to yield the title compound (224 mg, 0.598 mmol, 64.8% yield). Rf (50% EtOAc/heptane): sm=0.43; product=0.58. MS MH+=375.2
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C@@H:3]([N:7]1[C:16](=[O:17])[C:15]2=[CH:18][N:19](S(C3C=CC(C)=CC=3)(=O)=O)[C:13]3[C:14]2=[C:9]([C:10]([CH3:30])=[CH:11][N:12]=3)[CH2:8]1)[C:4]([OH:6])=[O:5].CO.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]([CH3:32])([CH3:31])[C@@H:3]([N:7]1[C:16](=[O:17])[C:15]2=[CH:18][NH:19][C:13]3[C:14]2=[C:9]([C:10]([CH3:30])=[CH:11][N:12]=3)[CH2:8]1)[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(S(=O)(=O)n2cc3c4c(c(C)cnc42)CN([C@@H](C(=O)O)C(C)(C)C)C3=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cnc2[nH]cc3c2c1CN([C@@H](C(=O)O)C(C)(C)C)C3=O
Temperature: 50 °C
Yield: 42 %

Procedure:
(R)-3,3-Dimethyl-2-(6-methyl-3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoic acid (36 mg, 0.079 mmol)) was dissolved in THF (3 mL), MeOH (3 mL) and aqueous NaOH (1N, 3 mL) in a 50 mL round bottom flask. The reaction mixture was heated at 50° C. for 30 min in an oil bath then cooled to room temperature. The solution was concentrated and purified by preparative HPLC (10-35% AcCN/H2O with 0.035% TFA) to give the title compound (10 mg, 42%). 1H NMR (500 MHz, CD3OD) δ 1.25 (s, 9H), 2.29 (s, 3H), 4.87 (s, 1H), 5.21 (d, J=19.5 Hz, 1H), 5.37 (d, J=19.5 Hz, 1H), 7.87 (s, 1H), 8.23 (s, 1H). [M+H] calc'd for C16H19N3O3, 302; found, 302.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH:20]=[O:21])[CH:7]=1)[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH2:20][OH:21])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(F)cc2C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)Cc1cccc(Oc2ccc(F)cc2CO)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 104.6 %

Procedure:
To [3-(4-fluoro-2-formyl-phenoxy)-phenyl]-acetic acid ethyl ester (0.35 g, 1.1 mmol) in MeOH (20 mL) was added sodium borohydride (0.052 g, 1.4 mmol), and the reaction was stirred for 10 minutes at room temperature. Once no starting material was seen by analytical tlc, the mixture was worked-up to give the desired product (0.35 g).
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:33]=[CH:32][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:30]=[CH:29][C:19]([C:20]([N:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[O:21])=[C:18]([OH:31])[CH:17]=2)=[CH:7][CH:6]=1.[C:34](OC1C=CC=CC=1)(=[O:36])[CH3:35].C(N(CC)CC)C>C(Cl)Cl>[C:34]([N:2]=[N:3][CH2:4][C:5]1[CH:33]=[CH:32][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:30]=[CH:29][C:19]([C:20]([N:22]([CH:26]([CH3:27])[CH3:28])[CH:23]([CH3:25])[CH3:24])=[O:21])=[C:18]([OH:31])[CH:17]=2)=[CH:7][CH:6]=1)(=[O:36])[CH3:35]
Reactant: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C=NN)cc2)cc1O)C(C)C
Reactant: CC(=O)Oc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N=NCc1ccc(OCCCCCOc2ccc(C(=O)N(C(C)C)C(C)C)c(O)c2)cc1
Reaction time: 8 h

Procedure:
A stirred solution of 4-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamide monohydrochloride (220 mg, 0.46 mmol) in 10 mL anhydrous methylene chloride is treated with phenyl acetate (73 uL, 0.51 mmol) and triethylamine (73 uL, 0.51 mmol). The solution is stirred overnight, concentrated in vacuo and the resulting liquid is purified by chromatography on silica gel (15 g) with 80-100% ethyl acetate/hexane as the eluent to afford 4-[5-[4-(acetyliminoaminomethyl)phenoxy]pentyloxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamide as a colorless foam; CHN calculated for C27H37N3O5 --0.5 H2O: Theory: % C: 65.83; % H: 7.78; % N: 8,53; Found: % C: 65.58; % H: 7.63; % N: 8,16.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)([CH3:10])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[SH2:24]>CN(C)C=O>[C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)([CH3:10])[C:8]([NH2:9])=[S:24])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: S
Reactant: CC(C#N)(c1ccccc1)c1ccccn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C(N)=S)(c1ccccc1)c1ccccn1

Procedure:
With continuous stirring, subject a mixture containing 6 g. of α-phenyl-α-(2-pyridyl) propionitrile and 5 ml. of triethylamine in 60 ml. of dimethylformamide to a stream of hydrogen sulfide for 24 hours. Pour the resulting solution into 200 ml. of ice water, filter, wash and dry the solids which are formed. Recrystallize the solids from acetonitrile to obtain the intermediate α-phenyl-α-(2-pyridyl) thiopropionamide, m.p. 186°-183° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([OH:23])=[C:17]([CH:22]=3)[C:18]([O:20]C)=[O:19])[N:9]=2)[CH:5]=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30].[OH-].[Na+]>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([OH:23])=[C:17]([CH:22]=3)[C:18]([OH:20])=[O:19])[N:9]=2)[CH:5]=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30]
Reactant: COC(=O)c1cc(-c2noc(-c3ccc(-c4ccccc4C)c(C)c3)n2)ccc1O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(O)c(C(=O)O)c3)no2)cc1C
Yield: 90 %

Procedure:
The title compound was prepared following procedure described for example 4, step 2, but starting from methyl 5-[5-(2,2′-dimethylbiphenyl-4-yl)-1,2,4-oxadiazol-3-yl]-2-hydroxybenzoate, obtained in step 1, and using 25 eq. of NaOH at 60° C. for 6 h. Solvents were concentrated and DCM (20 mL) was added. It was washed with HCl 1M. The organic layer was then dried over magnesium sulfate, filtered and concentrated to afford the title compound as a pale orange solid (18 mg; 90%). 1H NMR (DMSO-d6, 300 MHz) δ 8.54 (d, J=2.1 Hz, 1H), 8.22-8.17 (m, 2H), 8.08-8.05 (m, 1H), 7.38-7.28 (m, 4H), 7.19-7.12 (m, 2H), 2.14 (s, 3H), 2.04 (s, 3H). LC/MS (Method A): 385.0 (M−H)−. HPLC (Method A) Rt 5.49 min (Purity: 97.2%).
Reaction SMILES: C(O[C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:22])[C:13]3[C:14](=[C:16]([CH2:20][CH3:21])[N:17]([CH3:19])[N:18]=3)[N:15]=2)=[CH:8][C:7]([S:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH3:33])[CH2:28][CH2:27]2)(=[O:25])=[O:24])=[CH:6][N:5]=1)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:44][C@@H:45]([OH:48])[CH2:46][CH3:47]>>[CH2:20]([C:16]1[N:17]([CH3:19])[N:18]=[C:13]2[C:12](=[O:22])[NH:11][C:10]([C:9]3[C:4]([O:48][C@H:45]([CH3:44])[CH2:46][CH3:47])=[N:5][CH:6]=[C:7]([S:23]([N:26]4[CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH2:31]4)(=[O:25])=[O:24])[CH:8]=3)=[N:15][C:14]=12)[CH3:21]
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(C)nc2c(=O)[nH]1
Reactant: CC[C@@H](C)O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3O[C@H](C)CC)[nH]c(=O)c2nn1C
Temperature: 110 °C
Reaction time: 18 h
Yield: 17 %

Procedure:
The title compound of Example 78 (400 mg, 0.84 mmol) was added to a mixture of potassium bis(trimethylsilyl)amide (840 mg, 4.2 mmol) in (R)-2-butanol (4 ml) and the mixture stirred at 110° C. for 18 hours. The cooled mixture was concentrated under reduced pressure and the residue suspended in water (10 ml) and neutralised using 2N hydrochloric acid. This aqueous suspension was extracted with ethyl acetate (3×30 ml), the combined organic extracts washed with sodium hydroxide solution (20 ml), brine (2×30 ml), dried (Na2SO4) and evaporated under reduced pressure. The crude product was purified by is column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (100:0 to 97.5:2.5) and the product suspended in ether and evaporated under reduced pressure. This solid was recrystallised from hexane/ethyl acetate to afford the title compound (72 mg, 17%) as a white solid. [α]D=−20.88° (c=0.083, dichloromethane) Found: C, 54.65; H, 6.63; N, 19.25. C23H33N7O4S;0.5H2O requires C, 53.89; H, 6.69; N, 19.13% δ (CDCl3): 1.06 (6H, m), 1.40 (3H, t), 1.50 (3H, d), 1.86 (1H, m), 1.99 (1H, m), 2.42 (2H, q), 2.58 (4H, m), 3.04 (2H, q), 3.16 (4H, m), 4.09 (3H, s), 5.56 (1H, m), 8.62 (1H, s), 9.05 (1H, s), 10.70 (1H, s). LRMS: m/z 504 (M+1)+
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([Cl:10])[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:13]>O>[Cl:1][C:2]1[N:9]=[C:8]([Cl:10])[C:7]([F:11])=[CH:6][C:3]=1[C:4]([NH2:5])=[O:13]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Solvent: O
Product: NC(=O)c1cc(F)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 82 %

Procedure:
A 12-L 3-neck round bottom flask equipped with overhead stirrer, refluxing condenser, and N2 inlet/outlet was charged with 2,6-dichloro-5-fluoronicotinonitrile (2.0 kg, 1.0 eq). Concentrated sulfuric acid (4.93 L) was added and the mixture was stirred at RT until most of the brown solids had dissolved. Next, the reaction mixture was stirred at 65° C. for 1 h. The dark-brown solution was cooled to a temperature <10° C. using an ice bath. The reaction mixture was added to a 50-L round bottom flask, which contained de-ionized water (24.7 L) that had been cooled to a temperature <10° C., using a peristaltic pump. The reaction mixture was added to the water quench over a 2.3 h period, which kept the internal temperature of the mixture below 21° C. The resulting slurry was filtered through a Buchner funnel fitted with a Sharkskin filter paper. The 50-L RBF was rinsed with water (3×4 L) and the rinses were used to wash the filter cake. The filter cake was conditioned for 50 min, transferred to a drying tray, and was dried under high vacuum at 40-50° C. for 24 h and then at 20-25° C. for 18 h to give the title compound as a beige solid (896.4 g, 82%). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.94 (s, 1H), 8.10 (s, 1H), 8.24 (d, 1H). [M+H] calc'd for C6H3Cl2FN2O, 209. found, 209.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:9]=2[CH:10]=[O:11])=[CH:4][C:3]=1[CH3:18].[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:9]=2[CH2:10][OH:11])=[CH:4][C:3]=1[CH3:18]
Reactant: Cc1cc(C)c(C=O)c(-c2ccc(F)c(C)c2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C)c(CO)c(-c2ccc(F)c(C)c2)c1
Reaction time: 1 h
Yield: 98.9 %

Procedure:
2.90 grams (12 mmol) of 2-(4-fluoro-3-methyl-phenyl)-4,6-dimethylbenzaldehyde (prepared according to Stokker, Journ. Med. Chem., Vol. 29 p.170, 1986) was reduced with 0.454 grams (12 mmol) of sodium borohydride in ethanol (20 mL) at 0° C. The reaction was stirred 1 hr, quenched with aqueous ammonium chloride and the mixture extracted with ether. The organic portion was dried (MgSO4) and concentrated to give 2.90 grams of 2-(4-fluoro-3-methyl-phenyl)-4,6-dimethylbenzyl alcohol as an oil which solidified on standing. The crude solid was treated with 1.31 mL of thionyl chloride and heated on a steam bath for 1 hour. After cooling to room temperature, the crude mixture was taken up in water and extracted with ether. The ether was washed with water and dried(MgSO4), and concentrated to give an oily residue which was purified by silica gel chromatography (25% methylene chloride/75% hexane) to give 2.70 grams (85.6%) of 2-(4-fluoro-3-methyl-phenyl)-4,6-dimethylbenzyl chloride as a solid. 2.06 grams (7.84 mmol) of 2-(4-fluoro-3-methyl-phenyl)-4,6-dimethylbenzyl chloride was treated with ethyldiphenylphosphinite (2.08 grams, 9.01 mmol) and heated to 150° C. for 3 hrs. After cooling to room temperature, the crude mixture was purified by silicagel chromatography (10% acetone/90% methylene chloride) and the appropriate fractions concentrated and recrystallized from ether/hexane to provide the above-titled compound. MP 109-111° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[C:20]2[CH:21]=[CH:22][N:23]=[C:24]([O:25][CH3:26])[C:19]=2[C:18]2[C:13](=[CH:14][CH:15]=[N:16][CH:17]=2)[N:12]=1.[CH3:27][N:28](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[C:20]2[CH:21]=[CH:22][N:23]=[C:24]([O:25][CH3:26])[C:19]=2[C:18]2[C:13](=[CH:14][CH:15]=[N:16][CH:17]=2)[N:12]=1)[C:27]#[N:28]
Reactant: COc1nccc2c(Nc3c(Cl)cc(I)cc3Cl)nc3ccncc3c12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1nccc2c(Nc3c(Cl)cc(C#N)cc3Cl)nc3ccncc3c12
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
To a solution of N-(2,6-dichloro-4-iodophenyl)-10-methoxypyrido[4,3-c]-1,6-naphthyridin-6-amine (Example 152, Step 1) (1.0 g, 2.01 mmol) in DMF (10 mL) was added zinc cyanide (283 mg, 2.41 mmol) and Pd(Ph3P)4 (465 mg, 0.402 mmol). The reaction was stirred at 80 ° C. for 2.5 h in a sealed tube. After cooling to room temperature, the reaction was diluted with ethyl acetate and washed with water followed by brine. The organic layer was dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with methanol in dichloromethane to afford the title compound.