Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: IC1C=CC=CC=1S([O-])(=O)=O.[Na+].OOS([O-])=O.[K+].S([O-])([O-])(=O)=O.[Na+].[Na+].[CH2:26]([Si:28]([CH2:39][CH3:40])([CH2:37][CH3:38])[O:29][CH:30]1[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]1)[CH3:27]>C(OCC)(=O)C>[CH2:37]([Si:28]([CH2:26][CH3:27])([CH2:39][CH3:40])[O:29][CH:30]1[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]1)[CH3:38]
Reactant: CC[Si](CC)(CC)OC1CCC(O)CC1
Agent: O=S(=O)([O-])[O-]
Agent: O=S(=O)([O-])c1ccccc1I
Agent: O=S([O-])OO
Solvent: CCOC(C)=O
Product: CC[Si](CC)(CC)OC1CCC(=O)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
6.1 mg (0.02 mmol) of sodium 2-iodobenzenesulfonate prepared by Preparation Example 4, 0.49 g (0.8 mmol) of powdered Oxone (registered trademark), 0.5 g (3.5 mmol) of anhydrous sodium sulfate and 230 mg (1 mmol) of 4-(triethylsilyloxy)cyclohexanol were added to 5 ml of ethyl acetate, and the mixture was heated at 70° C. while being stirred under a nitrogen for eight hours. The later treatment was carried out in the same way as in Example 1, and then 4-(triethylsilyloxy)cyclohexanone was obtained. The yield of the obtained 4-(triethylsilyl oxy)cyclohexanone was determined and the result is shown in Table 2. (Yield 74%)
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.C([Li])CCC.COCN[C:16](=[O:27])[CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].[Cl-].[NH4+]>O1CCCC1>[CH3:25][C:22]([O:21][C:20](=[O:26])[NH:19][CH2:18][CH2:17][C:16]([C:2]1[CH:6]=[CH:5][O:4][CH:3]=1)=[O:27])([CH3:23])[CH3:24]
Reactant: Brc1ccoc1
Reactant: COCNC(=O)CCNC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC(=O)c1ccoc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
3-Bromofuran (5.88 g, 40 mmol) was dissolved in anhydrous tetrahydrofuran (60 ml) and the solution cooled to −78° C. n-Butyllithium (2.29M, 17.5 ml, 40 mmol) was added dropwise and the solution stirred for 1 h at −78° C. [3-(Methoxymethylamino)-3-oxopropyl]carbamic acid, 1,1-dimethylethyl ester as a solution in tetrahydrofuran (40 ml) was added dropwise over 1 h. The solution was stirred overnight whilst allowing to warm to room temperature. Aqueous saturated ammonium chloride solution (30 ml) was added and the mixture extracted with ethyl acetate (3×70 ml). The combined organic extracts were washed with water (3×30 ml), dried (sodium sulphate) and evaporated in vacuo. The residue was chromatographed on flash silica, eluting with hexane:ethyl acetate (7:3), to afford the title compound as a pale yellow solid (3.03 g, 63%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)[CH3:2]>C(Cl)Cl.CO>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Solvent: CO
Solvent: ClCCl
Product: CCN1CCN(Cc2ccc(N)cc2)CC1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 11.1 but using 1-ethyl-4-(4-nitro-benzyl)-piperazine (Step 12.2): ESI-MS: 220.1 [M+H]+; TLC: Rf=0.08 (DCM/MeOH+1% NH3aq, 9:1).
Reaction SMILES: [C:1]([C:3](=[CH2:51])[C:4]([NH:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]2[C:18](=[O:50])[N:19]([CH3:49])[CH:20]=[C:21]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([N:30]4[C:35](=[O:36])[C:34]5[S:37][C:38]6[CH2:43][CH2:42][CH2:41][CH2:40][C:39]=6[C:33]=5[CH:32]=[N:31]4)[C:24]=3[CH2:44][O:45]C(=O)C)[CH:22]=2)[N:11]=1)=[O:5])#[N:2].O[Li].O>C1COCC1.O>[C:1]([C:3](=[CH2:51])[C:4]([NH:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]2[C:18](=[O:50])[N:19]([CH3:49])[CH:20]=[C:21]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([N:30]4[C:35](=[O:36])[C:34]5[S:37][C:38]6[CH2:43][CH2:42][CH2:41][CH2:40][C:39]=6[C:33]=5[CH:32]=[N:31]4)[C:24]=3[CH2:44][OH:45])[CH:22]=2)[N:11]=1)=[O:5])#[N:2]
Reactant: C=C(C#N)C(=O)NCCOc1cccc(Nc2cc(-c3cc(F)cc(-n4ncc5c6c(sc5c4=O)CCCC6)c3COC(C)=O)cn(C)c2=O)n1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: C=C(C#N)C(=O)NCCOc1cccc(Nc2cc(-c3cc(F)cc(-n4ncc5c6c(sc5c4=O)CCCC6)c3CO)cn(C)c2=O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16 %

Procedure:
To a mixture of 117b (80 mg, 0.112 mmol) in THF (5 mL) was added LiOH.H2O (10 mg, 0.224 mmol) in H2O (5 mL) to pH 10-11. The reaction mixture was stirred at rt for 4 h and concentrated. The residue was purified by prep-HPLC to give 117 (12 mg, 16%) as white solid. The amide bond was partially cleaved under basic conditions. 1H NMR (500 MHz, CDCl3): δ8.57 (s, 1H), 8.29 (s, 1H), 7.99 (bs, 1H), 7.49 (t, J=8 Hz, 2H), 7.26-7.24 (m, 1H), 7.12 (d, J=10 Hz, 1H), 6.48 (d, J=8 Hz, 1H), 6.26 (d, J=8 Hz, 1H), 4.41 (t, J=5 Hz, 2H), 4.31 (bs, 2H), 4.00-3.98 (m, 1H), 3.72 (s, 3H), 3.63 (t, J=5.5 Hz, 1H), 3.58-2.56 (m, 1H), 2.99 (t, J=5 Hz, 2H), 2.87 (t, J=5 Hz, 2H), 2.00-1.96 (m, 4H). ESI-LCMS: m/z=668.0 [C34H30FN7O5S+H]+
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[N:28]=[C:27]([NH:29][S:30]([N:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH:26]=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([NH:29][S:30]([N:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CN(C)S(=O)(=O)Nc1cccc(Br)n1
Product: CN(C)S(=O)(=O)Nc1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1

Procedure:
The title compound was prepared by using the procedure listed in Example 1 with 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.10 g, 0.32 mmol) and N′-(6-bromopyridin-2-yl)-N,N-dimethylsulfamide (0.90 g, 0.32 mmol) as the starting materials.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[N:20]([C:21]5[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=5[CH3:28])[NH2:24])[CH:19]=[C:18]([CH3:29])[N:16]4[N:17]=3)[CH:10]=[N:9]2)=CC=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([S:43]([F:48])([F:47])([F:46])([F:45])[F:44])[CH:42]=1)[C:37](O)=[O:38].FC(F)(F)C(O)=O>>[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([S:43]([F:48])([F:44])([F:45])([F:46])[F:47])[CH:42]=1)[C:37]([NH:24][C:23]1[CH:25]=[CH:26][C:27]([CH3:28])=[C:21]([N:20]2[C:15]3[N:16]([N:17]=[C:13]([C:11]4[CH:12]=[N:8][NH:9][CH:10]=4)[CH:14]=3)[C:18]([CH3:29])=[CH:19]2)[CH:22]=1)=[O:38]
Reactant: COc1ccc(Cn2cc(-c3cc4n(-c5cc(N)ccc5C)cc(C)n4n3)cn2)cc1
Reactant: COc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)Nc2ccc(C)c(-n3cc(C)n4nc(-c5cn[nH]c5)cc34)c2)cc(S(F)(F)(F)(F)F)c1

Procedure:
60 mg (0.15 mmol) of the compound of Example 9A and 40 mg (0.15 mmol) of the compound of Example 25A were reacted analogously to the procedure of Example 10, except that here the reaction was stirred with trifluoroacetic acid at 80° C. only for 3 h (instead of 6 h). This gave 36 mg (43% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[CH2:24]([O:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O1CCOCC1>CO.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]>[CH2:24]([O:31][C:32]1[CH:37]=[C:36]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[CH:3]=2)[CH:35]=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(-c3cccc(OCc4ccccc4)c3)n3nccc3n2)cc1
Temperature: 110 °C
Yield: 0 %

Procedure:
A suspension of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 150 mmol), 3-Benzyloxyphenylboronic Acid (70 mg, 302 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9 mg, 12 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (670 microliters of 1,4-dioxane and 0.5 microliters of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 20 minutes. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC, 60-80% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (9.7 mg, 13%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6H) 5.21 (s, 2H) 6.59 (d, J=2.27 Hz, 1H) 7.27-7.32 (m, 1H) 7.36 (d, J=7.33 Hz, 1H) 7.39-7.44 (m, 1H) 7.49-7.54 (m, 2H) 7.49-7.57 (m, 1H) 7.54-7.59 (m, 1H) 7.60-7.67 (m, 3H) 7.75-7.79 (m, 1H) 8.01-8.06 (m, 3H) 8.19 (d, J=2.27 Hz, 1H) 11.26 (s, 1H). ESI-MS: m/z 479.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:4][C:3]=1[N+:18]([O-])=O.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[NH2:18][C:3]1[CH:4]=[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[CH:6]=[CH:7][C:2]=1[NH:1][C:23](=[O:24])[N:22]([CH3:26])[CH3:21]
Reactant: CN(C)C(=O)Cl
Reactant: Nc1ccc(NCc2ccc(Cl)cc2Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CN(C)C(=O)Nc1ccc(NCc2ccc(Cl)cc2Cl)cc1N
Yield: 35.1 %

Procedure:
A suspension of 31.2 g (100 mmol) 2-amino-5-(2,4-dichlorobenzylamino)-nitrobenzene is hydrogenated in a manner analogous with Example 1 (variant A) and worked up appropriately with 13.9 g (101 mmol) N,N-dimethylcarbamoyl chloride. 12.4 g of the end product are obtained in the form of the dihydrochloride. This forms colorless to pale pink crystals.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([O:14][C:15]([C:17]1([NH2:26])[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1)=[O:16])[CH3:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:12]([O:14][C:15]([C:17]1([NH:26][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=2[Br:1])[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: Cc1ccc(C(=O)O)c(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(NC(=O)c2ccc(C)cc2Br)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
To a solution of 2-bromo-4-methyl-benzoic acid (314 mg, 1.46 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (300 mg, 1.46 mmol), HATU (666 mg, 1.75 mmol) in anhydrous DMF (1.8 mL) is added DIPEA (381 μL, 2.19 mmol). The resulting solution is stirred at RT overnight. Poured reaction into water (10 mL) and extracted with EtOAc (3×5 mL). The combined organic layers and concentrated in vacuo. The residue is purified by flash column chromatography (12 g silica gel, gradient elution: 0-30% EtOAc in heptane) to give product (276) as off-white solid (445 mg, 76%).
Reaction SMILES: [C:1]1([N:7]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:29])C(=O)C1.O>C(Cl)Cl.C(#N)C>[Br:29][C:4]1[CH:3]=[CH:2][C:1]([N:7]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=3)=[CH:6][CH:5]=1
Reactant: O=c1c2ccccc2c2ccccc2n1-c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: O=c1c2ccccc2c2ccccc2n1-c1ccc(Br)cc1
Reaction time: 4 h

Procedure:
6.0 g (22 2 mmol) of 5-phenyl-5H-phenanthridin-6-one are initially introduced in 150 ml of CH2Cl2. A solution of 4 g (22 5 mmol) of NBS in 100 ml of acetonitrile is subsequently added dropwise at −15° C. with exclusion of light, the mixture is allowed to come to room temperature and is stirred at this temperature for a further 4 h. 150 ml of water are subsequently added to the mixture, which is then extracted with CH2Cl2. The organic phase is dried over MgSO4, and the solvents are removed in vacuo. The product is washed by stirring with hot hexane and filtered off with suction. Yield: 7.4 g (21 mmol), 80% of theory, purity according to 1H-NMR about 96%.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH2:8][OH:9].C(=O)([O-])[O-].[K+].[K+].[Si:16](Cl)([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.ClCCl.CO>CN(C)C=O>[Si:16]([O:9][CH2:8][C:7]1[NH:6][CH:5]=[N:4][C:3]=1[CH3:2])([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1nc[nH]c1CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: Cc1nc[nH]c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 3 h
Yield: 25.5 %

Procedure:
To 2.0 g(13.5 mmol) of 4-methyl-5-imidazolemethanol hydrochloride and 1.95 g(14.17 mmol) of potassium carbonate in 20 ml of dimethylformamide was added 3.88 g(14.17 mmol) of t-butyldiphenylsilylchloride was added dropwise thereto, and the resulting mixture was stirred for 3 hours. The solvent was removed under reduced pressure and the residue was dissolved in 20 ml of ethylacetate. The organic layer was washed with 20 ml of saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to column chromatography(eluent: dichloromethane/methanol=95/5, v/v) to give 1.22 g(3.44 mmol, Yield 26%) of the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([OH:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.C(N(CC)C(C)C)(C)C.Cl>C1COCC1.CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([OH:35])(=[O:33])=[O:34])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)=[O:12]
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: Nc1ccc(-c2ccc(S(=O)(=O)O)cc2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-c2ccc(S(=O)(=O)O)cc2)cc1)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.8 %

Procedure:
Benzofuran-2-carboxylic acid (310 mg, 1.9 mmol) was mixed with 3 ml of oxalyl chloride and refluxed for 1 h in the presence of a catalytic amount of DMF, then the excess oxalyl chloride was removed by vacuum. The residue was dissolved in 4 ml of dichloromethane and was added to a mixture of 400 mg (1.6 mmol) of 4′-amino-biphenyl-4-sulfonic acid, N,N-diisopropylethylamine (0.92 ml, 4 eq) and 4 ml of THF in an ice/water bath. The mixture was stirred at room temperature for 4 h. The reaction mixture was mixed with 2N HCl and in the process a suspension formed. The solid was collected by centrifugation and was washed with chloroform and 2N HCl to provide 540 mg of 4′-[(benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonic acid, obtained as pale brown solid.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[C:8]([CH2:12][CH:13]([N:15]([CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[CH2:16][CH2:17][CH3:18])[CH3:14])[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+]>O.C(O)(=O)C>[C:2]([NH:5][C:6]1[CH:7]=[C:8]([CH2:12][CH:13]([N:15]([CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[CH2:16][CH2:17][CH3:18])[CH3:14])[CH:9]=[CH:10][CH:11]=1)(=[O:1])[NH2:3]
Reactant: CCCN(CC1CCN(S(C)(=O)=O)CC1)C(C)Cc1cccc(N)c1
Reactant: N#C[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCCN(CC1CCN(S(C)(=O)=O)CC1)C(C)Cc1cccc(NC(N)=O)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.3 %

Procedure:
A solution of potassium cyanate (9 mg) in water (0.5 ml) was added to a solution of N-[2-(3-aminophenyl)-1-methylethyl]-N-propyl-(1-methanesulfonylpiperidin-4-ylmethyl)amine (40 mg) in water (2 ml) and acetic acid (1 ml). The mixture was stirred at ambient temperature for about 72 hours and then basified to pH 9 with 10% sodium hydroxide. The solution was extracted with dichloromethane, and the organic phase dried over sodium sulfate, filtered, evaporated in vacuo to give N-[2-(3-carbamoylaminophenyl)-1-methylethyl]-N-propyl-(1-methanesulfonylpiperidin-4-ylmethyl)amine (35 mg), M+H 411.2
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].N1C=CC=CC=1.Cl[C:12]([O:14][CH:15]([Cl:17])[CH3:16])=[O:13]>>[C:12](=[O:13])([O:4][CH:2]([CH3:3])[CH3:1])[O:14][CH:15]([Cl:17])[CH3:16]
Reactant: CC(C)O
Reactant: CC(Cl)OC(=O)Cl
Solvent: c1ccncc1
Product: CC(C)OC(=O)OC(C)Cl
Temperature: 25 °C
Yield: 88 %

Procedure:
To a solution of 2-propanol (2.66 mL, 34.97 mmol) and pyridine (3.39 mL, 41.96 mmol), pre-cooled in a dry-ice/acetone bath was slowly added 1-chloroethyl chloroformate. The resulting mixture was allowed to slowly warm to 25° C. overnight, with stirring. After concentration under reduced pressure the mixture was dissolved in ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 1-chloroethyl isopropyl carbonate as a pink/orange oil (5.11 g, 88% yield).
Reaction SMILES: [C:1]([C:4]1([C:7]2[CH:41]=[CH:40][CH:39]=[CH:38][C:8]=2[CH2:9][CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]4)=[N:23][CH:24]=3)[N:12]=2)[CH2:6][CH2:5]1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+].[OH-].[Na+]>C(Cl)Cl>[CH3:17][C:16]1[C:11]([CH2:10][CH2:9][C:8]2[CH:38]=[CH:39][CH:40]=[CH:41][C:7]=2[C:4]2([C:1]([NH2:2])=[O:3])[CH2:6][CH2:5]2)=[N:12][C:13]([NH:18][C:19]2[CH:24]=[N:23][C:22]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:21][CH:20]=2)=[N:14][CH:15]=1
Reactant: Cc1cnc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)nc1CCc1ccccc1C1(C(N)=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc(Nc2ccc(C3CCNCC3)nc2)nc1CCc1ccccc1C1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of tert-butyl 4-(5-((4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-methylpyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate A45 (0.200 g, 0.359 mmol) in DCM (10 mL) was treated with TFA (0.41 mL, 5.4 mmol) and stirred at room temperature for 4 hours. An extra aliquot of TFA (0.14 mL, 1.8 mmol) was added to the reaction mixture and stirring was continued for 1 hour at room temperature. Sat. aq. NaHCO3 (˜20 mL) was carefully added to the mixture followed by aq. NaOH (2 M, ˜20 mL). DCM was removed in vacuo and the aqueous mixture was extracted with EtOAc (3×30 mL). The organic extracts were combined, washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residue was dissolved in DCM before cyclohexane was added to form a white precipitate. The suspension was sonicated for 10 minutes and filtered to give the title compound A46 as a white solid (0.129 g, 79%). LCMS-D: rt 3.08 min; m/z 457 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].[H-].[Na+].[C:14](=O)([O:18]CC)[O:15][CH2:16][CH3:17].Cl>CN(C)C=O>[CH2:16]([O:15][C:14](=[O:18])[CH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3])[CH3:17]
Reactant: COc1ccc(C(C)=O)cc1
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a solution of 4-methoxyacetophenone (100 g, 0.66 mol) in dry dimethylformamide (400 mL), 60% sodium hydride (34.3 g, 0.85 mol) was added slowly at 10° C. under a nitrogen atmosphere. This mixture was stirred at 25° C. for 30 minutes and again cooled to 10° C. This was added to solution of diethyl carbonate (94.5 g, 0.80 mol) and dissolved in minimum quantity of dry dimethylformamide at the same temperature. The mixture was then stirred at 25° C. for 5 to 6 hours and poured into ice cold water (100 mL) with vigorous stirring. The mixture was then acidified (pH˜6-7) using cold 2 N hydrochloric acid and extracted with ethyl acetate. The organic layers were collected, combined, washed with water, dried over anhydrous sodium sulphate, filtered and concentrated under vacuum to afford the desired compound as yellow oil (133 g). Yield: 90%.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:28])=[C:12]([CH2:14][C:15]([NH:17][C:18]2([C:24]([O:26]C)=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:16])[CH:13]=1.O.Cl>CN(C)C=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:28])=[C:12]([C:14]2[C:15](=[O:16])[NH:17][C:18]3([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[C:24]=2[OH:26])[CH:13]=1
Reactant: COC(=O)C1(NC(=O)Cc2cc(Br)ccc2C)CCCCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Br)cc1C1=C(O)C2(CCCCC2)NC1=O
Temperature: 80 °C

Procedure:
1.71 g (15.2 mmol) of potassium tert-butoxide were added to 2.80 g (7.60 mmol) of the compound from Example 12A in 15 ml of N,N-dimethylformamide. The reaction mixture was heated at 80° C. for 15 minutes. After cooling, water was added and aqueous hydrogen chloride solution was added dropwise. The precipitate was filtered off with suction, washed with water and dried. This gave 2.33 g (90% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[C:29](Cl)=[O:30]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:29](=[O:30])[C:28]5[CH:27]=[C:26]([O:25][CH3:24])[C:34]([O:35][CH3:36])=[C:33]([O:37][CH3:38])[CH:32]=5)=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4cc(OC)c(OC)c(OC)c4)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-3,4,5-trimethoxy-benzamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 3,4,5-trimethoxybenzoyl chloride (204 mg, 0.89 mmol). The title compound was obtained as yellow powder (177 mg, 43%).