Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([C:11]#[N:12])=[C:6]([OH:10])[C:7]=1[C:8]#[N:9].CI.[C:15](=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C>C(#N)C>[CH3:1][S:2][C:3]1[S:4][C:5]([C:11]#[N:12])=[C:6]([O:10][CH3:15])[C:7]=1[C:8]#[N:9]
Reactant: CSc1sc(C#N)c(O)c1C#N
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CI
Solvent: CC#N
Product: COc1c(C#N)sc(SC)c1C#N

Procedure:
6 g of 2-methylthio-3,5-dicyano-4-hydroxythiophene 10 ml of methyl iodide, 10 g of potassium carbonate, and 3 ml of triethylamine are refluxed in 300 ml of acetonitrile while stirring. After 2 hours the reaction mixture is filtered warm and evaporated to dryness. The residue is taken up in 200 ml of methylene chloride and washed successively with a solution of potassium carbonate in water and with water. The methylene chloride solution is then dried and evaporated to dryness. After recrystallisation of the residue from isopropanol, the desired product is obtained in a yield of 4.0 g; melting-point 132° C.
Reaction SMILES: N12CCC(CC1)C(O)C2.[N+:10]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O)([O-:12])=[O:11].[NH2:21]/[C:22](/[CH3:28])=[CH:23]\[C:24]([O:26][CH3:27])=[O:25].[C:29]([O:35][CH2:36][CH2:37][C:38]#[N:39])(=[O:34])[CH2:30][C:31]([CH3:33])=O>>[CH3:33][C:31]1[NH:21][C:22]([CH3:28])=[C:23]([C:24]([O:26][CH3:27])=[O:25])[CH:16]([C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=2)[C:30]=1[C:29]([O:35][CH2:36][CH2:37][C:38]#[N:39])=[O:34]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(=O)OCCC#N
Reactant: COC(=O)/C=C(/C)N
Agent: OC1CN2CCC1CC2
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCC#N)C1c1cccc([N+](=O)[O-])c1

Procedure:
The compounds of the invention can be prepared by esterification of the enantiomers of methyl 3-carboxy-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridinedicarboxylate with the enantiomers of 1-azabicyclo[2.2.2]octan-3-ol (3-quinuclidinol). The acid may be prepared by condensation of 3-nitrobenzaldehyde with methyl 3-aminocrotonate and 2-cyanoethyl acetoacetate to afford 2-cyanoethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate which may be hydrolyzed with one equivalent of a suitable base (G.B. Patent 2122192), e.g. NaOH, to give methyl 3-carboxy-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridinedicarboxylate. Resolution of the acid is achieved by recrystallization of the cinchonidine (U.S. Pat. No. 4,920,225) addition salt from ethanol free chloroform. The enantiomers of 3-quinuclidinol are obtained by the procedure of B. Ringdahl, B. Resul and R. Dahlbom (Acta. Pharm. Seuc., 1979, 16, 281).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH:6][CH3:7].[C@@H:8]1([N:16]2[CH:23]=[CH:22][C:20](=[O:21])[NH:19][C:17]2=[O:18])[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[CH2:9]1.N1C=CC=CC=1.[CH3:30][O:31][C:32]1[CH:53]=[CH:52][C:35]([C:36](Cl)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[CH:34][CH:33]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.CO>[CH3:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2][CH3:1].[CH3:44][O:43][C:40]1[CH:39]=[CH:38][C:37]([C:36]([O:14][CH2:13][C@H:12]2[O:15][C@@H:8]([N:16]3[CH:23]=[CH:22][C:20](=[O:21])[NH:19][C:17]3=[O:18])[CH2:9][C@@H:10]2[OH:11])([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:35]2[CH:52]=[CH:53][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)=[CH:42][CH:41]=1
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: CC=CCCCC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
Compound (2a) (340 mg, 1.05 mmol) was azeotroped three times with anhydrous pyridine. The mixture was added with anhydrous pyridine (2.0 ml) and 4,4′-dimethoxytrityl chloride (427 mg, 1.26 mmol) which has been deaerated for 1 hour, and subsequently with DMAP (38 mg, 0.31 mmol). Finally, triethylamine (170 μl, 1.26 mmol) was added and the mixture was stirred for 13 hours at room temperature. After characterization by TLC (CHCl3:MeOH=95:5), the product was purified with silica gel column chromatography using the development solvent of CHCl3 and MeOH while varying the ratio of CHCl3:MeOH from 98:2 to 95:5 to obtain the target Compound (3a) as a pale yellow solid (304 mg, 0.49 mmol, yield 46%). The target compound was determined by 1H NMR for identification. Further, mass analysis was carried out by MALDI-TOF MS and it was identified as the target compound (calcd. for C37H43N2O7 [M+H]+ 627.306, found 627.455).
Reaction SMILES: C(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]=[O:18])CC(C)C.[OH:19][C:20]1C2C(=CC=CC=2)C(C=O)=[CH:22][CH:21]=1.BrCCC>>[CH2:20]([O:19][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:17]=[O:18])=[CH:7][CH:16]=1)[CH2:21][CH3:22]
Reactant: O=Cc1ccc(O)c2ccccc12
Reactant: CC(C)CCOc1ccc2ccccc2c1C=O
Solvent: CCCBr
Product: CCCOc1ccc(C=O)c2ccccc12

Procedure:
Prepared according to the Procedure for 2-(isopentyloxy)-1-naphthaldehyde using 4-hydroxy-1-naphthaldehyde and 1-bromopropane.
Reaction SMILES: [CH3:1][C:2](O)([CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])[CH3:3].C[Si]([C:21]#[N:22])(C)C.S(=O)(=O)(O)[OH:24].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][C:2]([NH:22][CH:21]=[O:24])([CH3:3])[CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: O=S(=O)(O)O
Reactant: CC(C)(O)CCNc1ccccc1[N+](=O)[O-]
Reactant: C[Si](C)(C)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(CCNc1ccccc1[N+](=O)[O-])NC=O
Temperature: 0 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
To a mixture of 2-methyl-4-[(2-nitrophenyl)amino]butan-2-ol (1.7 g, 7.8 mmol) and trimethylsilyl cyanide (4.2 mL, 31 mmol) was added concd. sulfuric acid at −30° C. and the mixture was warmed up to rt. After stirring for 24 h, the reaction mixture was cooled to 0° C. and to the mixture was added water and stirred for 30 min at rt. The mixture was poured into aq. potassium carbonate and extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with dichloromethane/methanol (25/1) to give 1.3 g (66%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5](Cl)=[O:6].[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[CH3:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5]([O:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: CC(C)CCC(=O)Cl
Reactant: Oc1ccccc1
Solvent: O
Product: CC(C)CCC(=O)Oc1ccccc1
Reaction time: 3 h
Yield: 88 %

Procedure:
4-Methylpentanoyl chloride (3.0 g, 22.3 mmol) was added dropwise to phenol (2.1 g, 22.3 mmol). After 3 hours, H2O was added and the reaction mixture was extracted with Et2O. The organic phase was washed with NaHCO3, then brine to neutrality, then dried (Na2SO4), concentrated and bulb-to-bulb distilled to afford the title compound in 88% yield.
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:14]3[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=3[C:16]([O:19][CH3:20])=[N:17][CH:18]=2)=[O:12])=CC=1)([O-])=O.[NH2:26][C:27]1[N:31]([CH3:32])[N:30]=[CH:29][C:28]=1[C:33]#[N:34]>>[C:33]([C:28]1[CH:29]=[N:30][N:31]([CH3:32])[C:27]=1[NH:26][C:11]([C:13]1[C:14]2[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=2[C:16]([O:19][CH3:20])=[N:17][CH:18]=1)=[O:12])#[N:34]
Reactant: Cn1ncc(C#N)c1N
Reactant: CCc1cc2c(C(=O)Oc3ccc([N+](=O)[O-])cc3)cnc(OC)c2o1
Product: CCc1cc2c(C(=O)Nc3c(C#N)cnn3C)cnc(OC)c2o1
Yield: 17.9 %

Procedure:
Starting from 2-ethyl-7-methoxyfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (100 mg) and 5-amino-1-methyl-1H-pyrazole-4-carbonitrile (71 mg). Purification by column chromatography on silica eluting with 50% hexane in ethyl acetate followed by trituration with ether gave the title compound (17 mg) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccn2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(OCc2ccccn2)cc1
Temperature: 75 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
2-[(4-Nitrophenoxy)methyl]pyridine (2.30 g, 10 mmol) was dissolved in ethanol (160 mL) and water (40 mL). NH4Cl (5.30 g) was added to the above mixture and heated to 70-80° C. To this reaction mixture was added iron powder (5.50 g) in portion wise manner under a vigorous stirring and the stirring was continued for 2 h. The reaction mixture was filtered through a Celite pad when hot and washed the filter bed with MeOH. The filtrate was concentrated, diluted with water, extracted with CH2Cl2 (3×75 mL), dried and concentrated to provide 2-[(4-aminophenoxy)methyl]pyridine as brown solid (1.735 g) in 86% yield. 1H NMR (CDCl3): δ 8.56 (m, 1H), 7.67 (m, 1H), 7.49 (d, 1H, J=7.8 Hz), 7.18 (m, 1H), 6.80 (d, 2H, J=8.7 Hz), 6.62 (d, 2H, J=8.7 Hz), 5.12 (s, 2H), 3.43 (br s, 2H); LCMS (m/z): 201 (MH+).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][CH:9]=1>C(NCC)C.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>[CH3:1][Si:2]([C:5]#[C:6][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:19])[C:15]([CH3:17])([CH3:16])[CH3:18])=[CH:10][CH:9]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)c1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CC(C)(C)C(=O)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.4 g Bis-(triphenylphosphine)-palladium dichloride and 0.19 g CuI are added, at room temperature, to a solution of 10.5 g trimethylsilylacetylene and 23.6 g 1-(4-bromophenyl)-2,2-dimethylpropan-1-one in 350 ml absolute diethylamine. The reaction mixture is stirred during 20 hours at room temperature, evaporated to dryness at the rotary evaporator and the residue extracted several times with toluene. The toluene is evaporated off and the remaining tacky oil chromatographed on a silica-gel column with hexane/toluene 2:1 as mobile phase to give 1-(4-trimethylsilylethynyl-phenyl)-2,2-dimethylpropan-1-one.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([S:17]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=3)(=[O:19])=[O:18])[CH:15]=2)[NH:10][CH:9]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:28]([O:27][C:24]1[CH:23]=[CH:22][C:21]([NH:20][S:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][CH:9]=[C:8]3[CH2:7][CH2:6][NH:5][C:1](=[O:3])[CH3:2])(=[O:19])=[O:18])=[CH:26][CH:25]=1)[CH3:29]
Reactant: CCOc1ccc(NS(=O)(=O)c2ccc3[nH]cc(CCN)c3c2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1ccc(NS(=O)(=O)c2ccc3[nH]cc(CCNC(C)=O)c3c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetyl chloride (0.6 ml) was added dropwise to a stirred solution of the product of Example 4 (3.1 g) in dry dimethylformamide (20 ml) containing triethylamine (3.3 ml) and the resulting suspension stirred at room temperature for 30 min. The suspension was partitioned between hydrochloric acid (2 N, 100 ml) and ethyl acetate (2×100 ml) and the combined extracts were washed with sodium carbonate (2 N, 100 ml) dried (MgSO4) and evaporated in vacuo to give an oil. The oil was purified by flash chromatography eluted with chloroform:methanol (19:1) to give the title compound as a foam (0.8 g), a sample of which (0.4 g) was crystallised from a mixture of ethyl acetate and hexane to give the title compound as a crystalline solid (0.3 g) m.p. 173°-175°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH2:15])[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[N:18]([CH3:20])[CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:45][N:46]([CH3:51])[CH2:47][C:48](O)=[O:49]>CN(C=O)C.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH:15][C:48](=[O:49])[CH2:47][N:46]([CH3:51])[CH3:45])[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[N:18]([CH3:20])[CH3:19]
Reactant: CN(C)CC(=O)O
Reactant: CN(C)c1cc(-c2ccc3nc(N)sc3c2)cnc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(N(C)C)c3)cc2s1
Temperature: 60 °C
Yield: 33.5 %

Procedure:
A mixture of 6-(6-chloro-5-(dimethylamino)pyridin-3-yl)benzo[d]thiazol-2-amine (70 mg, 230 μmol), HATU (210 mg, 552 μmol), and 2-(dimethylamino)acetic acid (45 mg, 436 μmol) in DMF (2.5 mL) was heated to 60° C. for 2 h. The solution was diluted with H2O (20 mL) until it became cloudy and cooled to rt. The mixture was filtered, washed with H2O (10 mL), Na2HCO3 (saturated, 5 mL), and H2O (5 mL). The filter was dissolved in MeOH (10%) in DCM and dried over MgSO4. The organic was filtered, concentrated to a yellow solid. This was further purified on silica using MeOH in EtOAc (0-5%) to give a light yellow solid. A second purification with 1:1 hexane-acetone removed the less polar impurity (NAc) effectively, affording a white solid (30 mg). MS (ESI, POS. ION) M/Z: calc'd for C18H20ClN5OS: 389.1. found: 390.1. 1H NMR (400 MHz, chloroform-d) δ ppm 2.43 (s, 3H) 2.93 (s, 3H) 3.25 (s, 2H) 7.52 (d, J=2.15 Hz, 1H) 7.63 (dd, J=8.41, 1.76 Hz, 1H) 7.87 (d, J=8.41 Hz, 1H) 7.99 (d, J=1.56 Hz, 1H) 8.27 (d, J=2.15 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[CH:21]=[C:20]([S:22][CH3:23])[N:19]=[C:18]([CH3:24])[N:17]=3)=[N:14][CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:30]>O1CCOCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[CH:21]=[C:20]([S:22]([CH3:23])=[O:30])[N:19]=[C:18]([CH3:24])[N:17]=3)=[N:14][CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(Nc2nccnc2-c2cc(SC)nc(C)n2)cn1
Solvent: C1COCCO1
Product: COc1ccc(Nc2nccnc2-c2cc(S(C)=O)nc(C)n2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A glass microwave reaction vessel was charged with N-(6-methoxypyridin-3-yl)-3-(2-methyl-6-(methylthio)pyrimidin-4-yl)pyrazin-2-amine (11 mg, 0.032 mmol) and 3-chloroperoxybenzoic acid (11.15 mg, 0.065 mmol) in dioxane (1 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was used for the next step reaction without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:22][C:21]3[C:16](=[N:17][C:18](Cl)=[CH:19][CH:20]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:22][C:21]3[C:16](=[N:17][C:18]([C:31]4[CH:32]=[CH:33][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:29][CH:30]=4)=[CH:19][CH:20]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3nc(Cl)ccc3o2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2cc3nc(-c4ccc(S(C)(=O)=O)cc4)ccc3o2)CC1
Temperature: 140 °C
Reaction time: 0.58 h

Procedure:
To a mixture of 4-(5-chloro-furo[3,2-b]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (50 mg) and 4-(methanesulfonyl)phenyl boronic acid (45 mg) in [1,4]dioxane (1.5 mL) in a microwave oven suited vessel charged with a stir bar a 2 M aqueous Na2CO3 solution (1904) is added. The mixture is sparged with argon for 10 min and Pd(PPh3)4 (21 mg) is added. The vessel is capped and the mixture is stirred under microwave irradiation at 140° C. for 35 min. After cooling the mixture to room temperature, dichloromethane and water are added. The organic phase is washed with brine, dried (MgSO4) and the solvent is evaporated. The crude product is purified by HPLC on reversed phase (MeOH/H2O/TFA). Yield: 25 mg (37% of theory); LC (method 2): tR=1.36 min; Mass spectrum (ESI+): m/z=457 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:24])[CH:5]=[CH:6][CH:7]=1.Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:24])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(Cl)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(Cl)c1
Reaction time: 0.05 h
Yield: 95.7 %

Procedure:
40% Methanolic Triton B (0.053 mL, 0.12 mM) was added to a solution of the 9-[(3-chlorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (33.2 mg, 0.12 mM) in 2 mL DMF at room temperature. After 3 minutes, t-butyl bromoacetate (53.8 mg, 0.27 mM) was added and the resultant mixture stirred at room temperature for 20 h. The mixture was diluted with ethyl acetate, washed four times with H2O, once with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 42.1 mg (95%) of the {9-[(3-chlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, tert-butyl ester as a white solid. 1H NMR (DMSO-d6) δ 7.6 (d, 1H, J=8 Hz), 7.5-6.8 (m, 10H), 6.55 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.8 (s, 2H), and 1.45 (s, 9H). IR (CHCl3, cm−1) 3450, 3400, 1744, 1676, 1591, 1457, 1369, and 1150. MS (FD) m/e 464, 466.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][CH2:59][C@@H:60]([OH:62])[CH3:61]>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:58][CH2:59][C@H:60]([OH:62])[CH3:61])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@H](O)CN
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC[C@@H](C)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (S)-1-aminopropan-2-ol. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 (d, J=6.1 Hz, 3H) 1.12-1.41 (m, 3H) 1.55-1.87 (m, 8H) 1.70-1.88 (m, 4H) 3.21 (q, J=6.3 Hz, 1H) 3.32 (s, 3H) 3.77 (m, 1H) 3.94 (s, 3H) 4.16 (t, J=13.0 Hz, 2H) 4.49 (quin., J=12.1 Hz, 1H) 7.53 (d, J=8.6 Hz, 1H) 7.58 (s, 1H) 8.14 (d, J=8.3 Hz, 1H) 8.23 (s, 1H) 8.41-8.47 (m, 1H) 8.51-8.57 (m, 1H). [M+H] calc'd for C25H32F2N6O4 519. found 519.
Reaction SMILES: [OH-].[K+].[OH:3][NH:4]C(=O)OC(C)(C)C.[N+]([C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:16]=1[C:17]#[N:18])([O-])=O.O>CN(C=O)C>[NH2:18][C:17]1[C:16]2[C:19]([N+:23]([O-:25])=[O:24])=[CH:20][CH:21]=[CH:22][C:15]=2[O:3][N:4]=1
Reactant: CC(C)(C)OC(=O)NO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1noc2cccc([N+](=O)[O-])c12
Reaction time: 20 h
Yield: 21.7 %

Procedure:
To potassium hydroxide (0.58 g, 10.3 mmol) and tert-butyl N-hydroxycarbamate (1.38 g, 10.3 mmol) in DMF (30 iml) was added 2,6-dinitrobenzonitrile (2.0 g, 10.3 nmmol) and the mixture was stirred for 20 h. Water was added. The whole was extracted with ether, the ether was dried (sodium sulphate) and evaporated. Flash column chromatography on silica gel, eluting with ethyl acetate/dichloromethane, gave the product (0.4 g), MS (+CI) 180 ([M+H]+), 1H NMR (CDCl3) 8.13 (1H, d), 7.78 (1H, d), 7.68 (1H, dd), 5.43 (2H, s).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[NH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17].CC([O-])(C)C.[K+]>CS(C)=O>[CH2:2]([N:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=C1CCCN1
Reactant: CCCCCCCCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCCCCCCCN1CCCC1=O

Procedure:
22.1 g 1-Bromodecane (0.1 mol), 8.5 g (0.1 mol) of 2-pyrrolidone and 11.2 g (0.1 mol) of potassium tert-butylate were stirred in 100 ml of absolute DMSO for one hour. The DMSO was removed under reduced pressure, the residue taken up with diethyl ether, and washed with water (2 times). After drying with anhydrous MgSo4 and evaporating, the residue was distilled in vacuo. A first fraction, boiling between 140° and 147° C./1.2 mm Hg was discarded. The second fraction 17.4 g of pure product, b.p. 148° C./1.2 mm Hg.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[CH3:7][N:8]1[C:17]2[C:16](=[O:18])[NH:15][C:14]3[CH:19]=[CH:20][CH:21]=[CH:22][C:13]=3[NH:12][C:11]=2[C:10]([CH3:23])=[CH:9]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Br:1][CH2:2][CH2:3][C:4]([N:12]1[C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[NH:15][C:16](=[O:18])[C:17]2[N:8]([CH3:7])[CH:9]=[C:10]([CH3:23])[C:11]1=2)=[O:5]
Reactant: O=C(Cl)CCBr
Reactant: Cc1cn(C)c2c1Nc1ccccc1NC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cn(C)c2c1N(C(=O)CCBr)c1ccccc1NC2=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
A solution of 3.42 g of 3-bromopropionyl chloride in 20 ml of dioxane is added dropwise to 4.54 g of 1,3-dimethyl-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]benzodiazepin-10-one, 5.0 g of powdered anhydrous potassium carbonate and 80 ml of dry dioxane in the course of 10 minutes at from 50° to 60° C., and the mixture is stirred at this temperature for a further 2 hours. The solvent is stripped off in vacuo, and the resulting solid residue is stirred with 300 ml of ice water and filtered off. 5.1 g of the title compound of m.p. 194° to 195° C. (D.) are obtained after recrystallization from isopropanol.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4](=[O:10])[NH:5][C:6]([CH3:9])=[CH:7][CH:8]=1.C1COCC1.CO>C(Cl)Cl.O=[Mn]=O>[CH3:9][C:6]1[NH:5][C:4](=[O:10])[C:3]([CH:2]=[O:1])=[CH:8][CH:7]=1
Reactant: Cc1ccc(CO)c(=O)[nH]1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(C=O)c(=O)[nH]1
Temperature: 57 °C
Yield: 101 %

Procedure:
3-(hydroxymethyl)-6-methyl-2(1H)-pyridinone (2.0 g, 13 mmol) was dissolved in CH2Cl2(80 mL), THF (80 mL) and MeOH (5 mL), MnO2 (3.7 g, 43 mmol) was added. The reaction mixture was heated at 57° C. for 18 hours. The reaction was filtered through a pad of Celite® and concentrated to give a solid (1.8 g, 90%). LCMS (ES+) m/z 138 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:15])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccc(F)cc1
Reaction time: 2 h
Yield: 104.1 %

Procedure:
To a solution of 4-fluorophenylacetic acid (1, scheme 1) (26.5 g, 172 mmol) in DCM (93 mL) was added oxalyl chloride (2 eq., 30.1 mL, 344 mmol) over 5 min and DMF (0.005 eq., 0.067 mL, 0.86 mmol) over 1 min. The reaction mixture was stirred at r.t for 2 h then concentrated. The residual DCM was removed as an azeotrope with toluene (2×20 mL) to afford intermediate 2-(4-fluorophenyl)acetyl chloride (1a) (30.85 g, 179 mmol, assumed quantitative yield) as yellow oil. Part of that material was used as is in the next step.