Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:14][N:15]([CH3:17])[CH3:16])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Cc1ccc([N+](=O)[O-])c(F)c1
Temperature: 125 °C
Yield: 63 %

Procedure:
A mixture of 2-fluoro-4-methyl-1-nitro-benzene (3 g, 19.3 mmol), N,N-dimethylformamide dimethylacetal (10 mL) and 3 mL of DMF (30 mL) was heated at 125° C. for 1 hour. The mixture was cooled and concentrated under reduced pressure to give a purple solid. Trituration with hexanes gave the pure title product (2.5 g, yield: 63%). MS (ESI): 211 [M+H]+.
Reaction SMILES: CS[C:3]([NH:8][CH2:9][C:10]#[CH:11])=[CH:4][N+:5]([O-:7])=[O:6].Cl.N[CH2:14][CH2:15][SH:16]>>[N+:5]([CH:4]=[C:3]([NH:8][CH2:9][C:10]#[CH:11])[CH2:14][CH2:15][SH:16])([O-:7])=[O:6]
Reactant: NCCS
Reactant: C#CCNC(=C[N+](=O)[O-])SC
Agent: Cl
Product: C#CCNC(=C[N+](=O)[O-])CCS

Procedure:
A solution of the product of Step A of Example 2 is reacted with about an equimolar amount of cysteamine hydrochloride and about two equivalents of base, and the title product is produced.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([CH2:7][NH:8]S(C(C)(C)C)=O)[O:4][N:3]=1.[ClH:15].O1CCOCC1>CO>[ClH:15].[Br:1][C:2]1[CH:6]=[C:5]([CH2:7][NH2:8])[O:4][N:3]=1
Reactant: CC(C)(C)S(=O)NCc1cc(Br)no1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NCc1cc(Br)no1
Reaction time: 2 h

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid (3-bromo-isoxazol-5-ylmethyl)-amide (128 mg, 0.455 mmol) in MeOH (5 mL) was added a 4 M solution of HCl in dioxane (0.350 mL, 1.40 mmol) dropwise. After 2 hours and 10 minutes, the reaction mixture was concentrated in vacuo to afford the title compound which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([O:31][CH3:32])([C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]OS(C1C=CC(C)=CC=1)(=O)=O.[NH3:33]>CO>[CH3:1][O:2][C:3]([O:31][CH3:32])([C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:33]
Reactant: N
Reactant: COC(CCCCCCOS(=O)(=O)c1ccc(C)cc1)(OC)c1ccc(C(F)(F)F)cc1
Solvent: CO
Product: COC(CCCCCCN)(OC)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Toluene-4-sulfonic acid 7,7-dimethoxy-7-[4-(trifluoromethyl)phenyl]heptyl ester (1.82 g, 3.835 mmol) was dissolved in a magnetically stirred solution of 7 M NH3 in methanol (30 ml) and stirred at room temperature for 72 hours. After removal of the solvent in vacuo, the residue was dissolved again in dichloromethane and washed with saturated aqueous NaHCO3. The organic layer was subsequently dried over Na2SO4, filtered and concentrated in vacuo to give crude 7,7-dimethoxy-7-[4-(trifluoromethyl)phenyl]heptylamine (1.43 g) which was not further purified. 1H-NMR (400 MHz, CDCl3) δ 0.88-0.95 (m, 2H), 1.12-1.16 (m, 4H), 1.33-1.38 (m, 2H), 1.83-1.88 (m, 2H), 2.59-2.65 (m, 2H), 3.10-3.26 (m, 8H, including —OMe singlet at 3.14), 7.56 (d, J˜8, 2H), 7.60 (d, J˜8, 2H).
Reaction SMILES: F[C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:14])[CH3:13])[CH2:8][CH2:7]1)=O.[C:20]([O:24][CH3:25])(=[O:23])[CH2:21][SH:22].[H-].[Na+]>C1COCC1>[CH3:25][O:24][C:20]([C:21]1[S:22][C:2]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=2[C:4]=1[CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:14])[CH3:13])[CH2:8][CH2:7]1)=[O:23]
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Reactant: COC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1sc2cc(F)ccc2c1C1CCN(C(C)=O)CC1
Temperature: 25 °C
Yield: 65.1 %

Procedure:
To a stirred solution of 33.6 g (0.126 mol) of 1-[4-(2,4-difluoro-benzoyl)-piperidin-1-yl]-ethanone and 13 mL (145 mol) of methyl thioglycolate in 320 mL dry THF was added 5.8 g (145 mol) of 60% sodium hydride in mineral oil in portions. The reaction mixture was heated to reflux overnight, allowed to cool to room temperature and the solvent removed under reduced pressure. The residue was then partitioned between 300 mL of CH2Cl2 and 200 mL of water. The aqueous layer was further extracted with CH2Cl2 (2×500 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a residue which was then triturated with hexanes/EtOAc to give 27.5 g (65%) of the desired product as a white solid. MS (electrospray): exact mass calculated for C17H18FNO3S, 335.1; m/z found, 336.1 [M+H]+. 1H NMR (DMSO-d6, 400 MHz, a mixture of amide rotamers): 7.12 (m, 2H), 6.92 (dt, J=8.41, 1.77 Hz, 1H), 4.43 (d, J=3.79 Hz, 1H), 4.43-4.36 (m, 1H), 3.82 (bt, J=14.65 Hz, 1H), 3.57 (s, 3H), 2.92-2.79 (m, 1H), 2.38-2.34 (m, 1H), 1.94 (s, 1.5H), 1.93 (s, 1.5H), 1.86-1.72 (m, 1H), 1.47-1.38 (m, 1H), 1.38-1.27 (m, 0.5H), 1.27-1.16 (m, 1H), 1.15-1.03 (m, 0.5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[C:31]1[NH:35][C:34](=[O:36])[O:33][N:32]=1)[O:6][CH2:7][C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:23][O:24]C(=O)C.[OH-].[Li+]>CO>[OH:24][CH2:23][C:9]1[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=2)[S:12][C:8]=1[CH2:7][O:6][C:5]1[CH:28]=[CH:29][C:30]([C:31]2[NH:35][C:34](=[O:36])[O:33][N:32]=2)=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2COC(C)=O)ccc1-c1noc(=O)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CO)ccc1-c1noc(=O)[nH]1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 48.9 %

Procedure:
To a suspension of 0.5 g of acetic acid 5-[3-methoxy-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethyl ester in 5 mL of methanol at 0° C. was added 0.22 g of lithium hydroxide. The resulting solution was stirred for 45 minutes at 0° C. then it was allowed to warm up to room temperature. The solvent was partly removed under reduced pressure and ethyl acetate/1 molar aqueous solution of KH2PO4 was added. The organic layer was separated and the aqueous layer extracted three times with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. 40 mL of Ethyl acetate was added to the residue and, after stirring for 30 minutes, the resulting solid was collected by filtration to give 225 mg of 3-{4-[4-hydroxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-4H-[1,2,4]oxadiazol-5-one as a beige solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6](=[O:25])[CH:7]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:15](I)=[C:14]([Cl:24])[CH:13]=2)[CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:2]1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[CH:36][C:37]3[C:38]([CH:42]=2)=[N:39][O:40][N:41]=3)O1.[F-].[Cs+].O.CCOC(C)=O>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:1]1([CH2:4][O:5][C:6](=[O:25])[CH:7]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:15]([C:34]3[CH:35]=[CH:36][C:37]4[C:38]([CH:42]=3)=[N:39][O:40][N:41]=4)=[C:14]([Cl:24])[CH:13]=2)[CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:2]1
Reactant: CC1(C)OB(c2ccc3nonc3c2)OC1(C)C
Reactant: CC(C)CC(C(=O)OCC1CC1)c1cc(Cl)c(I)c(OCC2CC2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)CC(C(=O)OCC1CC1)c1cc(Cl)c(-c2ccc3nonc3c2)c(OCC2CC2)c1
Temperature: 100 °C
Yield: 41.2 %

Procedure:
To a solution of 2-(3-chloro-5-cyclopropylmethoxy-4-iodo-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.27 g, 0.57 mmol) in DME (anhydrous, 10 mL) under argon atmosphere were added 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[1,2,5]oxadiazole (0.15 g, 0.61 mmol), CsF (0.2 g, 1.32 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.021 g, 0.029 mmol, need 0.06 mmol to complete the reaction!). The reaction mixture was refluxed for 18 h (oil bath, 100° C.). A mixture water/EtOAc (15 mL/15 mL) was added and the layers were separated. The organic phase was dried over MgSO4, then evaporated to give a crude yellow oil, which was purified by silica gel gradient column chromatography using Heptane-EtOAc (20:1-9:1) to give 2-(4-benzo[1,2,5]oxadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.11 g, 41%) of as a yellowish oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.83 (d, J=9.3 Hz, 1H), 7.77 (s, 1H), 7.36-7.33 (m, 1H), 7.11 (s, 1H), 6.91 (s, 1H), 4.02-3.81 (m, 4H), 3.67 (t, J=7.7 Hz, 1H), 2.03-1.96 (m, 1H), 1.74-1.65 (m, 1H), 1.60-1.45 (m, 1H), 1.20-1.05 (m, 2H), 0.96 (d, J=6.3 Hz, 6H), 0.57-0.47 (m, 4H), 0.28 (br s, 2H), 0.19 (br s, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 173.4, 157.0, 149.2, 148.3, 142.0, 138.7, 135.4, 133.5, 126.4, 121.6, 117.4, 114.9, 110.6, 73.4, 69.8, 49.8, 42.8, 26.1, 22.5, 22.4, 10.0, 9.8, 3.3, 3.1
Reaction SMILES: [Cl:1][CH:2]([P:17](=[O:30])([O:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[O:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[P:3](=[O:16])([O:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[O:4][CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[Cl-].[Br:32][O-].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:32][C:2]([Cl:1])([P:3](=[O:16])([O:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[O:4][CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)[P:17](=[O:30])([O:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[O:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=P(OC1CCCC1)(OC1CCCC1)C(Cl)P(=O)(OC1CCCC1)OC1CCCC1
Reactant: [O-]Br
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: O=P(OC1CCCC1)(OC1CCCC1)C(Cl)(Br)P(=O)(OC1CCCC1)OC1CCCC1
Temperature: 10 °C

Procedure:
4.8 g (0.01 moles) of tetracyclopentyl (monochloromethylene)bisphosphonate (31P-NMR (CDCl3): δ 12.44 ppm, 2JPH =17.7 Hz) are dissolved in 20 ml of carbontetrachloride and 0.55 g of bensyltriethylammonium chloride and 20 ml of a 10% sodium hypobromite solution are added while cooling and stirring at about 10° C. The mixture is stirred vigorously for 30 min at about 10° C. and the organic phase is separated, washed with water, dried (Na2SO4) and filtered. The filtrate is evaporated in a vacuum, whereby about 5.0 g (90% of the theor.) of tetracyclopentyl (bromochloromethylene)bisphosphonate (31P-NMR (CDCl3): δ 7.68 ppm) is obtained as a colourless oil at a concentration of >80%.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)=[O:2].C([O-])(O)=O.[Na+].[NH2:18][CH2:19][C:20]([CH3:23])([OH:22])[CH3:21]>CO>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:18][CH2:19][C:20]([OH:22])([CH3:23])[CH3:21])(=[O:11])=[O:10])=[CH:5][CH:4]=1)=[O:2]
Reactant: CC(C)(O)CN
Reactant: O=Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)(O)CNS(=O)(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-formyl-benzene sulfonyl chloride (1.0 g) in MeOH was added NaHCO3 (0.425 g), followed by 1-amino-2-methylpropan-2-ol (0.566 g). The reaction mixture was stirred for 1 h at RT, then filtered through Celite and the solvent removed under reduced pressure to provide 4-formyl-N-(2-hydroxy-2-methylpropyl)-benzene sulfonamide.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[N+:15]([C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[CH:21]=[CH:22][C:23](O)=O)([O-:17])=[O:16]>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:23](/[CH:22]=[CH:21]/[C:20]3[CH:26]=[CH:27][CH:28]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc([N+](=O)[O-])c3)nc2n(CC)c1=O
Yield: 44.9 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 2.5 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 2.68 g (13.9 mmol) of 3-nitrocinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 2.01 g (yield 30%) of Compound 159 as a yellow powder.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[CH:10][C:4]=2[N:3]=1>CN(C=O)C.[O-2].[Mn+4].[O-2]>[CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:4]=2[N:3]=1
Reactant: Cc1nc2cc(CO)ccc2[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CN(C)C=O
Product: Cc1nc2cc(C=O)ccc2[nH]1

Procedure:
24.4 g (0.15 mol) of 18c in 400 ml of DMF are stirred with 84.8 g (0.975 mol) of manganese(IV) oxide at room temperature for 3 days in analogy to Example 8b.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)[N:3]=1.Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:18]([O:17][C:15](=[O:16])[CH2:14][N:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[N:3]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Fc1cccc(-c2ncc[nH]2)n1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1ccnc1-c1cccc(F)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.5 %

Procedure:
A mixture of 2-Fluoro-6-(1H-imidazol-2-yl)pyridine (410 mg; 2.51 mmol), tert-butyl bromoacetate (539 mg; 2.76 mmol), potassium carbonate (520 mg; 3.77 mmol), and N,N-dimethylformamide (20 mL) is stirred at room temperature for 16 h. Water (60 mL) is added and the mixture extracted with ethyl acetate (3×70 mL). The organic extracts are washed with water (3×40 mL) and brine (1×40 mL), dried (MgSO4), and concentrated to give [2-(6-Fluoropyridin-2-yl)-imidazol-1-yl]acetic acid tert-butyl ester as an orange oil (630 mg). 1H NMR (CDCl3) δ 8.12 (dd,1H), 7.82(q,1H), 7.16(s,1H), 6.98(s,1H), 6.81(dd,1H), 5.14(s,2H), 1.44s,(9H), LCMS: 276.1(M−).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])C.O.[CH3:7][O:8][P:9]([O-:13])([O:11][CH3:12])=[O:10].[CH3:14][NH+:15]1[CH2:19][CH2:18][N:17](C)[CH:16]1Cl>C(O)C>[CH3:7][O:8][P:9]([O-:13])([O:11][CH3:12])=[O:10].[CH3:1][NH+:3]1[CH2:4][CH2:5][N:17]([CH3:18])[CH:16]1[N:15]([CH3:19])[CH3:14]
Reactant: CCNCC
Reactant: CN1CC[NH+](C)C1Cl
Agent: COP(=O)([O-])OC
Solvent: CCO
Solvent: O
Product: CN(C)C1N(C)CC[NH+]1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.9 %

Procedure:
1.14 g (15.59 mmol) of diethylamine and 10 ml of water are added with stirring to 2.0 g (7.73 mmol) of 1,3-dimethyl-2-chloroimidazolidinium dimethylphosphate. The reaction mixture is stirred for 10 minutes at room temperature, and 10 ml of ethanol are subsequently added. The solution is extracted 5 times with 30 ml of dichloromethane. Water is distilled off from the aqueous phase. The residue is dried for 4 hours under a reduced pressure of 7 Pa at an oil-bath temperature of 70-80° C., giving 1.85 g of 1,3-dimethyl-2-dimethylaminoimidazolidinium dimethylphosphate, corresponding to a yield of 81%.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:22]([CH3:23])=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][C:16]=2[CH3:24])[C:8]=1[CH3:25])[CH2:4][CH3:5])[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:16]([CH3:24])=[CH:17][C:18]([CH2:19][OH:20])=[CH:21][C:22]=2[CH3:23])[C:8]=1[CH3:25])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C=O)cc2C)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(CO)cc2C)c1C
Temperature: 25 °C

Procedure:
A mixture of 4-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-benzaldehyde and sodium borohydride in methanol was stirred at room temperature. After standard work-up procedure and purification, the title compound was obtained as a solid. 1H NMR(CDCl3) d 7.06(s,2H), 6.08(s,1H), 4.64(s,2H), 3.74(d,1H), 3.33(m,1H), 2.14(s,3H)., 2.13(s,3H), 2.11(s,6H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:14])([CH3:13])[C:10](O)=[O:11])[CH:6]=[CH:5][C:4]=1[C:15]1[CH:20]=[C:19]([CH2:21][O:22][CH3:23])[CH:18]=[CH:17][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.[CH2:34]([NH2:38])[CH:35]([CH3:37])[CH3:36].C(Cl)CCl>C(Cl)Cl.CN(C=O)C>[CH2:34]([NH:38][C:10](=[O:11])[C:9]([C:7]1[CH:6]=[CH:5][C:4]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([CH2:21][O:22][CH3:23])[CH:20]=2)=[C:3]([O:2][CH3:1])[CH:8]=1)([CH3:13])[CH3:14])[CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)CN
Reactant: COCc1cccc(-c2ccc(C(C)(C)C(=O)O)cc2OC)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCc1cccc(-c2ccc(C(C)(C)C(=O)NCC(C)C)cc2OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
To a solution of 2-(2-methoxy-5′-(methoxymethyl)biphenyl-4-yl)-2-methylpropanoic acid (example 27a) (315 mg, 1 mmol) in DCM (10 mL) and DMF (1 mL) were added HOBt (135 mg, 1 mmol) and isobutyl amine (98 μL, 1 mmol) followed by EDC (197 mg, 1 mmol). The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with water and brine, dried over MgSO4, filtered and evaporated. The residue was purified by preparative RP HPLC (water-acetonitrile) to give a colorless oil that was further evaporated from EtOH (3×) and dried to yield 150 mg (41%) of the product. 1H NMR (400 MHz, dMSO): δ 0.76-0.77 (t, 3H), 1.49 (s, 6H), 1.10-1.72 (m, 1H), 2.85-2.88 (t, 2H), 3.30 (s, 3H), 3.74 (s, 3H), 4.44 (s, 2H), 6.96-6.98 (m, 2H), 7.22-7.26 (m, 2H), 7.36-7.38 (m, 4H); MS+H (370.2).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:4][CH2:3]1.[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O.[OH-].[Na+]>[C:15]1([CH2:14][O:21][C:22]([N:2]2[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:4][CH2:3]2)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)CCCC1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 5 °C

Procedure:
Either solid 4-(4-piperidyl) butyric acid hydrochloride (124 kg) is dissolved in water (600 kg), or the 16% aqueous solution of 4-(4-piperidyl)butyric acid hydrochloride prepared in step 3 (777 kg), is diluted with aqueous sodium hydroxide (289 kg) in a 1600 liter glass lined reactor cooled at 5° C. Benzylchloroformate (112 kg) is added over a period of 2-3 hours and the solution is heated to about 25° C. The reaction mixture is extracted with methyl tert-butyl ether (476 kg). The aqueous layer is then acidified with hydrochloric acid (187 kg) and extracted with toluene (450 kg). The organic layer is washed with water (240 kg) and dried by azeotropic distillation at atmospheric pressure under nitrogen. The resulting solution of 1-[(phenylmethoxy)carbonyl]-4-piperidinebutanoic acid in toluene is used as is in step 5. Weight of the product in solution: 179 kg. Quality: about 35% w/w in toluene.
Reaction SMILES: [C:1]1([CH2:11][C:12]#[N:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+].[N-:16]=[N+:17]=[N-:18].[Na+].O>CN(C=O)C>[C:1]1([CH2:11][C:12]2[NH:18][N:17]=[N:16][N:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1cccc2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2c(Cc3nnn[nH]3)cccc2c1
Temperature: 125 °C
Reaction time: 16 h

Procedure:
A mixture of the above acetonitrile (5.40 g, 32 mmol), ammonium chloride (2.59 g, 48 mmol) and sodium azide (3.15 g, 48 mmol) in N,N'-dimethylformamide (100 ml) was stirred at 125° C. for 16 hours. After cooling the mixture was poured into water (300 ml) and extracted with ethyl acetate (2×150 ml) The combined organic phases were washed with water (100 ml) and evaporated in vacuo. The residue was crystallised from diethyl ether (20 ml), filtered off and washed with diethyl ether affording 1.86 g (27%) of the title compound as a solid.
Reaction SMILES: [CH3:1][N:2]([CH:17]([CH3:19])[CH3:18])[C:3]1[C:4](=[O:16])[NH:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([OH:15])=O)=[CH:8][CH:7]=2.[CH3:20][C:21]([NH2:24])([CH3:23])[CH3:22].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>ClCCl>[C:21]([NH:24][C:13]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4](=[O:16])[C:3]([N:2]([CH3:1])[CH:17]([CH3:19])[CH3:18])=[N:12]2)=[O:15])([CH3:23])([CH3:22])[CH3:20]
Reactant: CC(C)N(C)c1nc2cc(C(=O)O)ccc2[nH]c1=O
Reactant: CC(C)(C)N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Product: CC(C)N(C)c1nc2cc(C(=O)NC(C)(C)C)ccc2[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[methyl(propan-2-yl)amino]-2-oxo-1,2-dihydroquinoxaline-6-carboxylic acid (1 g, 3.83 mmol) in dichloromethane (50 ml) was added 2-methylpropan-2-amine (560 mg, 7.66 mmol), TEA (967 mg, 9.56 mmol), and T3P (1.83 g, 7.66 mmol). The resulting solution was stirred overnight at room temperature and then concentrated in vacuo to afford N-tert-butyl-3-[methyl(propan-2-yl)amino]-2-oxo-1,2-dihydroquinoxaline-6-carboxamide as yellow oil (1.5 g, crude).
Reaction SMILES: [Br:1][C:2]1[C:12]2[C:13]3[C:5]([CH2:6][CH:7]([OH:14])[C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.Cl[Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CN=C1>C1COCC1.C(OCC)C>[Br:1][C:2]1[C:12]2[C:13]3[C:5]([CH2:6][CH:7]([O:14][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OC1Cc2ccc(Br)c3cccc1c23
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](OC1Cc2ccc(Br)c3cccc1c23)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 5-bromo-1,2-dihydro-1-acenaphthylenol (0.25 g, 1 mmol) in dry THF (30 mL) was added chloro(tert-butyl)diphenylsilane (0.275 g, 1 mmol) and imidazole (0.34 g, 5 mmol), and the reaction stirred at room temperature under nitrogen for 18 h. The mixture was diluted with diethyl ether, filtered through a pad of silica, and evaporated in vacuo. Purification by flash chromatography on silica, eluting with ethyl acetate/hexane (1:9 to 1:1), yielded the title compound as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:11]2[NH:19][C:14]3=[CH:15][N:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)[OH:10])[CH:5]=[CH:6][C:7]=1[Cl:8]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[NH:19][C:14]3=[CH:15][N:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OC(c1ccc(Cl)c(Cl)c1)c1cc2ccncc2[nH]1
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)c(Cl)c1)c1cc2ccncc2[nH]1
Yield: 45 %

Procedure:
(3,4-Dichlorophenyl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (99 mg, 45%) was prepared as a yellow solid following the procedure described for Example 100 using (3,4-dichlorophenyl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methanol (Example 113) and tetrahydrofuran as a solvent: mp 274-277° C. dec.; 1H NMR (500 MHz, DMSO-d6) δ7.24 (1H, s), 7.70 (1H, d, J=5.5 Hz), 7.87-7.95 (2H, m), 8.14 (1H, d, J=1.9 Hz), 8.22 (1H, d, J=5.6 Hz), 8.93 (1H, s), 12.50 (1H, s); ESI MS m/z 291 [C14H8Cl2N2O+H]+; HPLC (Method A) >99% (AUC), tR=17.4 min.