Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH:21]=[CH:20][CH2:19]1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:33])C=1>>[C:11]([O:10][C:8](=[O:9])[N:7]([CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH:21]2[CH:20]([O:33]2)[CH2:19]1)[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:24])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N(CCCC1CC=CCC1)C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)N(CCCC1CCC2OC2C1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 89.8 %

Procedure:
N-tert-Butoxycarbonyl-(3-cyclohex-3-enyl-propyl)-carbamic acid tert-butyl ester (12.2 g, 29.4 mmol, corrected) was treated with 3-chloroperbenzoic acid (70% purity, 8.7 g, 35.3 mmol, corrected) according to the method of Example 7 Step B and stirred at room temperature for 4.5 hours. After work up the title compound (9.38 g, 90% yield) was obtained as light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]2[O:6][C:7]3[CH:32]=[CH:31][CH:30]=[CH:29][C:8]=3[CH2:9][N:10]([C:11]([NH:13][C:14]([CH3:28])([CH3:27])[CH2:15][NH:16]C(=O)OCC3C=CC=CC=3)=[O:12])[C:4]=2[CH:3]=1>CCO.C1COCC1.[Pd]>[NH2:16][CH2:15][C:14]([NH:13][C:11]([N:10]1[CH2:9][C:8]2[CH:29]=[CH:30][CH:31]=[CH:32][C:7]=2[O:6][C:5]2[CH:33]=[CH:34][C:2]([Cl:1])=[CH:3][C:4]1=2)=[O:12])([CH3:28])[CH3:27]
Reactant: CC(C)(CNC(=O)OCc1ccccc1)NC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(CN)NC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Yield: 32.4 %

Procedure:
The title product of Example 18 (6.5 g, 13.4 mmol) dissolved in a mixture of EtOH and THF was hydrogenated in a standard Parr apparatus using-3% Pd on carbon as catalyst. The reaction was run under a H2 pressure of 5 psi for 5.5 hours at 40° C. to produce the crude product. This material was purified by HPLC on silica gel to yield 1.5 g of the title material.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.[OH-].[Na+]>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH:6][S:24]([C:21]1[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:23][CH:22]=1)(=[O:26])=[O:25]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](C)NS(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C

Procedure:
Alanine methyl ester hydrochloride (7.0 g, 50.0 mmol) is dissolved in methylene chloride (100.0 mL) and triethylamine (20.0 mL, 143.0 mmol). To this solution is added 4-methoxybenzenesulfonyl chloride (10.3 g, 50.0 mmol), and the reaction is stirred at room temperature briefly. The reaction is made basic with 1N sodium hydroxide, and washed with methylene chloride. The combined organic layers are dried (Na2SO4), and the solvent is evaporated. Hexane is added to the residue and the precipitate is collected to give N-[4-methoxybenzenesulfonyl]-alanine methyl ester.
Reaction SMILES: [Br:1][C:2]([CH3:7])([CH3:6])[C:3](Br)=[O:4].[CH3:8][C:9]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:10]=1[NH2:11].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]([CH3:7])([CH3:6])[C:3]([NH:11][C:10]1[C:12]([CH3:17])=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=1[CH3:8])=[O:4]
Reactant: CC(C)(Br)C(=O)Br
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(NC(=O)C(C)(C)Br)c(C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
2-bromo-2-methylpropanoyl bromide (4.50 g, 19.57 mmol) was added to a mixture of 2,4,6-trimethylaniline (2.41 g, 17.78 mmol), triethylamine (3.60 g, 35.56 mmol), and CH2Cl2 (20 ml) at 0° C. under Ar atmosphere. The cooling bath was removed after the addition was completed, and the reaction mixture was stirred at room temperature for 1.5 hour, after which time the mixture was diluted with CH2Cl2 (20 ml) and added aqueous solution of NH4Cl. After the aqueous phase was separated, the organic layer was washed with brine and dried over anhydrous MgSO4. Filtration and concentration of the filtrate gave 2-bromo-N-mesityl-2-methylpropanamide as a pale yellow solid (5.05 g, 17.78 mmol, 100%). A solution of this amide (284 mg, 1.00 mmol) in dry THF (5 ml) was added to a mixture of sodium hydride (60% in mineral oil, 80 mg, 2.00 mmol), aniline (112 mg, 1.20 mmol) and THF (5 ml), and the resulting mixture was stirred for overnight at room temperature. The mixture was then added an aqueous solution of NH4Cl (15 ml), extracted with ethyl acetate (20 ml×2), and the combined organic layer was washed with brine then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum, and the residue was purified by column chromatography on silica (eluent: Hexane/Ethyl acetate=5/1˜4/1) to give the amide as a white solid (255 mg, 0.86 mmol, Y=86%). 1H NMR (300 MHz, CDCl3): δ 8.35 (s, 1H), 7.25-7.17 (m, 2H), 6.84-6.71 (m, 5H), 3.98 (s, 1H), 2.23 (s, 3H), 2.11 (s, 6H), 1.63 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 173.8, 144.5, 136.4, 134.8, 131.0, 129.0, 119.2, 116.2, 58.4, 26.2, 20.8, 18.6. IR: 3341 (m), 3310 (s), 2987 (w), 1666 (s), 1607 (m), 1488 (s), 1376 (m), 1318 (m), 1264 (m), 1210 (m), 1162 (m), 850 (m), 749 (s), 696 (m) cm−1. HRMS Calc'd for C19H24N2O: 297.1967. Meas: 297.1956.
Reaction SMILES: C1(S[CH2:8][N:9]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([O:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:15]=[CH:16][C:17]=3[O:21][CH2:22][CH3:23])[S:10]2(=[O:12])=[O:11])C=CC=CC=1.S(Cl)([Cl:36])(=O)=O>ClCCl>[Cl:36][CH2:8][N:9]1[C:19](=[O:20])[C:18]2[C:13](=[C:14]([O:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:15]=[CH:16][C:17]=2[O:21][CH2:22][CH3:23])[S:10]1(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOc1ccc(OCC(=O)OC(C)(C)C)c2c1C(=O)N(CSc1ccccc1)S2(=O)=O
Solvent: ClCCl
Product: CCOc1ccc(OCC(=O)OC(C)(C)C)c2c1C(=O)N(CCl)S2(=O)=O
Yield: 95 %

Procedure:
By the method of part E of Example 45 2-phenylthiomethyl-4-ethoxy-7-(t-butoxycarbonylmethoxy)saccharin (1.92 g) was reacted with sulfuryl chloride (0.54 g) in dichloromethane at about 5° C. and purified with hexane affording 2-chloromethyl-4-ethoxy-7-(t-butoxycarbonylmethoxy)saccharin, 1.54 g, 95% yield, mp 117°-119° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[CH:13]=[C:12]([C:22]([OH:24])=O)[CH:11]=1)#[N:2].Cl.Cl.[CH3:27][C:28]1[N:33]=[CH:32][C:31]([C@H:34]([NH2:36])[CH3:35])=[CH:30][CH:29]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([CH:16]([OH:21])[C:17]([F:19])([F:18])[F:20])[CH:13]=[C:12]([C:22]([NH:36][C@@H:34]([C:31]2[CH:32]=[N:33][C:28]([CH3:27])=[CH:29][CH:30]=2)[CH3:35])=[O:24])[CH:11]=1)#[N:2]
Reactant: Cc1ccc([C@@H](C)N)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(O)C(F)(F)F)c2)c(C#N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3ccc(C)nc3)cc(C(O)C(F)(F)F)c2)c(C#N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2′-cyano-4′-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)biphenyl-3-carboxylic acid (32 mg, 0.095 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (50 mg, 0.24 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (100 mg, 0.26 mmol), and N,N-diisopropylethylamine (300 μL, 1.72 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product as a light color solid.
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])C=CC=CC=1.[CH3:29][C:30]1[O:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[CH3:34][C:33]1[O:36][C:30](/[CH:29]=[CH:9]/[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:31][CH:32]=1
Reactant: CCOC(=O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(C=O)o1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC/C=C/c1ccc(C)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of triphenyl-(3-ethoxycarbonylpropyl)phosphonium bromide (2.27 g, 5 mmol) and 5-methylfurfural (0.55 g, 5 mmol) in 5 mL of dry tetrahydrofuran, a 1 M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours and quenched with 2 N hydrochloric acid solution. The reaction mixture was extracted with ethyl acetate and the combined organic layers were dried over magnesium sulfate, concentrated and chromatographed eluting with 5% ethyl acetate/hexane to yield the title product: 1H NMR (300 MHz, CDCl3) δ 6.16 (d, J=3.05 Hz, 1H), 5.97 (dd, J=3.22, 0.85 Hz, 1H), 5.42 (dt, J=11.44, 7.11 Hz, 1H)), 4.14 (q, J=7.2 Hz, 2H), 2.76 (m, 2H), 2.47 (t, J=7.46 Hz, 2H), 2.31 (s, 3H), 1.25 (t, J=7.12 Hz, 3H); MS (DCI/NH3)(M+H)+ m/z 209.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][O:6][C:7]1[C:12]([NH2:13])=[C:11]([O:14][CH3:15])[N:10]=[C:9]([CH3:16])[N:8]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[N:13]([C:12]1[C:7]([O:6][CH3:5])=[N:8][C:9]([CH3:16])=[N:10][C:11]=1[O:14][CH3:15])=[C:1]=[S:2]
Reactant: COc1nc(C)nc(OC)c1N
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc(C)nc(OC)c1N=C=S
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
Thiophosgene (7.7 mL, 101 mmol) was added dropwise to a stirred mixture of 4,6-dimethoxy-2-methylpyrimidin-5-amine (14.2 g, 84.3 mmol) in tetrahydrofuran, (110 mL) and saturated aqueous sodium hydrogen carbonate (110 mL) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with n-hexane to give the title compound as a brown powder (12.5 g, 59.0 mmol, 70%).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH2:15]=O>C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH3:15])[CH2:11][CH2:12]2)=[CH:13][CH:14]=1
Reactant: Brc1ccc(CC2CCNCC2)cc1
Reactant: C=O
Solvent: O=CO
Product: CN1CCC(Cc2ccc(Br)cc2)CC1
Temperature: 150 °C
Yield: 98.1 %

Procedure:
A mixture of 4-(4-bromobenzyl)-piperidine (290 mg, 1.14 mmol), formic acid (12 mL) and 37% aqueous formaldehyde (0.30 mL, 3.75 mmol) was divided into three portions. Each portion was heated at 150° C. for 5 minutes in a microwave reactor. The combined cold mixture was loaded onto a 5 g SCX-2 cartridge which was then washed with methanol (30 mL) then 2 N ammonia in methanol (50 mL). Concentration of the combined basic fractions in vacuo gave the title compound (300 mg, 98%) as a colourless oil. LCMS (Method B): RT=2.18 min, M+H+=268, 270.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[C:12]([F:20])[CH:11]=2)[C:5]([C:21]#[N:22])=[C:4]([S:23][CH2:24][C:25]2[N:26]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[O:28][CH:29]=2)[N:3]=1.[NH2:37][CH2:38][CH2:39][OH:40]>C1COCC1>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([C:27]2[O:28][CH:29]=[C:25]([CH2:24][S:23][C:4]3[C:5]([C:21]#[N:22])=[C:6]([C:10]4[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[C:12]([F:20])[CH:11]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:37][CH2:38][CH2:39][OH:40])[N:3]=3)[N:26]=2)=[CH:35][CH:34]=1
Reactant: NCCO
Reactant: N#Cc1c(Cl)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)c(F)c1
Solvent: C1CCOC1
Product: N#Cc1c(NCCO)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
25 mg (0.046 mmol) of 2-chloro-6-({[2-(4-chlorophenyl)-1,3-oxazol-4-yl]methyl}sulfanyl)-4-[3-fluoro-4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrile (Example 125A) are initially charged in 1 ml of THF, 6 μl of 2-aminoethanol are added and the mixture is stirred at room temperature for 30 minutes. The reaction mixture is then purified directly by preparative HPLC (mobile phase gradient: acetonitrile/water 10:90→95:5). This gives 24 mg (94% of theory) of the target compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([C:23]5[CH:28]=[CH:27][C:26]([CH2:29][OH:30])=[CH:25][CH:24]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[C:31]1(C)C=CC(S(O)(=O)=O)=CC=1.CO>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([C:23]5[CH:24]=[CH:25][C:26]([CH2:29][O:30][CH3:31])=[CH:27][CH:28]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(CO)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: COCc1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2C)cc1
Yield: 23.1 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(4′-(hydroxymethyl)-6-methylbiphenyl-3-yl)cyclopropanecarboxamide (40 mg, 0.10 mmol), para-toluenesulfonic acid (24 mg, 0.13 mmol) and MeOH (53 μL, 1.3 mmol) were dissolved in toluene (2.0 mL) and irradiated in the microwave at 140° C. for 10 minutes. Volatiles were removed in vacuo and crude product was purified by reverse phase HPLC to afford 1-(benzo[d][1,3]dioxol-5-yl)-N-(4′-(methoxymethyl)-6-methylbiphenyl-3-yl)cyclopropanecarboxamide (9.6 mg, 23%). ESI-MS m/z calc. 415.5, found 416.5 (M+1)+; retention time 3.68 minutes.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C@@H:17]4[CH2:21][CH2:20][NH:19][CH2:18]4)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:3][CH2:2]1.C[Si]([N:31]=[C:32]=[O:33])(C)C>>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C@@H:17]4[CH2:21][CH2:20][N:19]([C:32]([NH2:31])=[O:33])[CH2:18]4)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)[C@@H]3CCNC3)ccc2n1CC1CC1
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)[C@@H]3CCN(C(N)=O)C3)ccc2n1CC1CC1

Procedure:
The title compound was prepared according to the procedure described in STEP D of Example 6 using 1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-5-[(3R)-pyrrolidine-3-sulfonyl]-1H-1,3-benzodiazole (STEP D) and trimethylsilyl isocyanate instead of methanesulfonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH3:17]N(C(N(C)C)C)C>FC(F)(F)C(O)=O>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[C:13](=[CH2:17])[CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: CC(N(C)C)N(C)C
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Solvent: O=C(O)C(F)(F)F
Product: C=C1CCc2nc3ccccc3c(N)c2C1=O
Temperature: 100 °C

Procedure:
In 25ml of trifluoroacetic acid cooled in ice was dissolved 5.00 g of 9-amino-3,4-dihydroacridin-1(2H)-one. To the solution was added dropwise 6.70ml (2.09 eq) of bisdimethylaminoethane over 5 minutes and thereafter the mixture was maintained at 90°100° C. for 5 hours during which the starting material was converted to a mixture of intermediate and exo-methylene products. The reaction mixture was poured into ice/NaOH to make it basic and the precipitate was extracted with several portions of 5:1 dichloromethane/MeOH. The combined extracts were evaporated to a residue. The residue was refluxed in toluene for 5 hours during which the intermediate was converted to the end product. The reaction mixture was evaporated to a residue which was purified by chromatography on silica gel (EtOAc) to yield about 2 g of a solid. This was recrystallized from dichloromethane/EtOAc to yield 1.79 g (34%) of product as a solid, melting point 119°-193° C.
Reaction SMILES: O[CH:2]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)[CH2:3][CH:4]=[CH2:5].O.CC(C)=[O:14]>>[OH:14][CH:6]1[CH:2]([CH2:3][CH:4]=[CH2:5])[C:8](=[O:7])[CH:9]=[CH:10]1
Reactant: C=CCC(O)c1ccco1
Reactant: CC(C)=O
Solvent: O
Product: C=CCC1C(=O)C=CC1O
Temperature: 55 °C
Reaction time: 96 h
Yield: 43 %

Procedure:
Into 350 ml of a water-acetone (1:6 by volume) mixture, was dissolved 10 g of 2-(1-hydroxy-3-butenyl)furan. To the solution heated at 55° C. under reflux, was added dropwise 6.6 g of polyphosphoric acid. After having been stirred at 55° C. for 96 hours, the reaction mixture was freed from the acetone by distillation and the residue was extracted twice with 300 ml of ether. The extract solution was washed with an aqueous sodium hydrogencarbonate solution, then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and freed from the solvent by distillation to obtain 8.5 g of a concentrate. The concentrate was purified by a column chromatography using 100 g of a silica gel (Wako Gel C-200) and a toluene-ether (2:1 by volume) mixture as eluent, to obtain 4.3 g (43% yield) of 4-hydroxy-5-allyl-2-cyclopentenone.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.C(N(CC)CC)C.[F:33][C:34]([F:41])([F:40])[CH2:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[F:33][C:34]([F:41])([F:40])[CH2:35][S:36]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1)(=[O:38])=[O:37]
Reactant: Cn1cc(-c2cc(N)ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(-c2cc(NS(=O)(=O)CC(F)(F)F)ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a solution of Example 3 (0.05 g, 0.151 mmol) and triethylamine (0.053 mL, 0.377 mmol) in dichloromethane (1.0 mL) was added dropwise 2,2,2-trifluoroethanesulfonyl chloride (0.036 g, 0.196 mmol). The reaction mixture was stirred for 1 hour at room temperature and then purified by flash chromatography (silica gel, 0-5% methanol in dichloromethane) to afford 0.050 g (68%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 3.49 (s, 3H) 4.55 (q, J=9.91 Hz, 2H) 6.28 (t, J=2.38 Hz, 1H) 6.86 (d, J=7.54 Hz, 2H) 6.95-7.07 (m, 2H) 7.20-7.31 (m, 5H) 7.40 (d, J=2.78 Hz, 1H) 10.43 (s, 1H) 12.02 (s, 1H). MS (APCI+) m/z 478 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[Br:19][CH2:20][C:21](Br)=[O:22]>ClCCl>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([NH:1][C:21](=[O:22])[CH2:20][Br:19])[CH:3]=1
Reactant: O=C(Br)CBr
Reactant: COC(=O)c1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(NC(=O)CBr)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a solution of methyl 3-aminobenzoate (4.53 g, 30.0 mmol) and triethylamine (3.54 g, 4.88 mL, 35.0 mmol) in dichloromethane (100 mL), at 0° C. while stirring, was added bromoacetyl bromide (6.66 g, 2.9 mL, 33.0 mmol) dropwise. After the addition, the mixture was stirred at room temperature overnight and passed through a short silica pad. The crude product, 3-(2-bromoacetylamino)benzoic acid methyl ester (8.09 g, 99.1%), obtained after the removal of the solvent (>99% by LC/MS, MS (ES+) m/z: 272, 274) was used without further purification.
Reaction SMILES: CS(C)=O.[I-].[CH3:6][S+](C)(C)=O.[H-].[Na+].[CH3:13][C:14]([CH3:24])([CH3:23])[C:15]([C:17]1[CH:18]=[N:19][CH:20]=[N:21][CH:22]=1)=[O:16]>O1CCCC1>[C:14]([C:15]1([C:17]2[CH:22]=[N:21][CH:20]=[N:19][CH:18]=2)[CH2:6][O:16]1)([CH3:24])([CH3:23])[CH3:13]
Reactant: CC(C)(C)C(=O)c1cncnc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(C)(C)C1(c2cncnc2)CO1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under an atmosphere of argon, 10 ml of dimethyl sulphoxide are slowly added dropwise to 0.96 g (4.3 mmol) of trimethylsulphoxonium iodide and 0.17 g of sodium hydride (60%, 4.3 mmol). The reaction mixture is then stirred at room temperature for 15 min, and 0.65 g (3.9 mmol) of 2,2-dimethyl-1-(5-pyrimidinyl)-1-propanone, dissolved in 2 ml of tetrahydrofuran, is added. The reaction mixture is stirred at 50° C. for 90 min. The reaction mixture is then concentrated under reduced pressure, and saturated aqueous sodium chloride solution and ethyl acetate are added to the residue. The organic phase is separated off dried over sodium sulphate, filtered and concentrated. This gives 0.70 g (99%) of the desired product, which is reacted without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:22][C:21](=[O:23])[C:20]4[C:15](=[C:16]([CH3:27])[CH:17]=[C:18]5[CH:26]=[N:25][NH:24][C:19]5=4)[N:14]=3)=[CH:11][C:10]([O:28][CH3:29])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[C:31]1([NH2:37])([CH:34]2[CH2:36][CH2:35]2)[CH2:33][CH2:32]1.C(N(CC)CC)C>CN(C)C=O>[C:31]1([NH:37][C:21]([C:20]2[C:15]([NH:14][C:13]([C:12]3[N:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[N:9]=[C:10]([O:28][CH3:29])[CH:11]=3)=[O:22])=[C:16]([CH3:27])[CH:17]=[C:18]3[C:19]=2[NH:24][N:25]=[CH:26]3)=[O:23])([CH:34]2[CH2:36][CH2:35]2)[CH2:33][CH2:32]1
Reactant: COc1cc(-c2nc3c(C)cc4cn[nH]c4c3c(=O)o2)n(-c2ncccc2Cl)n1
Reactant: NC1(C2CC2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)Nc2c(C)cc3cn[nH]c3c2C(=O)NC2(C3CC3)CC2)n(-c2ncccc2Cl)n1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a solution of 500 mg of the above 7-[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazol-3-yl]-5-methyl-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 8 mL of N,N-dimethylformamide is added 244 mg (1.83 mmol) of bicyclopropyl-1-ylamine hydrochloride and 340 μL (2.44 mmol) of triethylamine. The reaction is stirred at 70° C. for 16 hours and then concentrated in vacuo. The residue is taken-up with water and ethyl acetate. The phases are separated and the aqueous layer is washed with ethyl acetate. The combined organic layers are washed several times with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (SiO2, hexanes/ethyl acetate 3:7) affords 90 mg (15% over two steps) of product as a pale yellowish solid; LC/MS:506/508 (M+H)+, m.p.: 150-154° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25]>>[C:24]([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:12]([CH2:11]/[CH:10]=[CH:9]/[C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)[S:13]([CH3:16])(=[O:15])=[O:14])#[N:25]
Reactant: CS(=O)(=O)NC/C=C/c1cc(Cl)cc(Cl)c1
Reactant: N#CCCCCCCBr
Product: CS(=O)(=O)N(C/C=C/c1cc(Cl)cc(Cl)c1)CCCCCCC#N
Yield: 79.7 %

Procedure:
In an analogous manner to the procedure described in Step A of Example 1, trans-N-[3-(3,5-dichloro-phenyl)-allyl]-methanesulfonamide (500 mg, 2.45 mmol) was alkylated with 7-bromoheptanenitrile (781 mg; 2.94 mmol) at room temperature over 24 h to provide the title compound of Step A (760 mg). 1H NMR (CDCl3 400 MHz) δ 7.26 (m, 3H), 6.49 (d, 1H), 6.22 (m, 1H), 3.98 (m, 2H), 3.22 (t, 2H), 2.88 (s, 3H), 2.36 (t, 2H), 1.68-1.35 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)[Cl:13].C(Cl)(=O)C(Cl)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([Cl:13])=[O:8]
Reactant: ClCCl
Reactant: Cc1ncc(Cl)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: Cc1ncc(Cl)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Chloro-2-methyl-nicotinic acid (4.15 g, 24.2 mmol) is placed in a flask with DCM (100 mL) and oxalyl chloride (3.68 g, 29 mmol). DMF (200 μL) is added and the reaction mixture is stirred at r.t. for 1 hour (gas evolution). The mixture is filtered and the solvent is removed in vacuo to afford the title product which is used in the next step without further purification.