Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=[CH:37][C:38](N2CCSC2=S)=[O:39])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]>O1CCCC1>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=[CH:37][C:38]([N:21]2[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][O:14][CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:19][CH2:20]2)=[O:39])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: COc1ccc(C=CC=CC(=O)N2CCSC2=S)cc1OC
Reactant: c1ccc(C(OCCCN2CCNCC2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C=CC=CC(=O)N2CCN(CCCOC(c3ccccc3)c3ccccc3)CC2)cc1OC
Yield: 89 %

Procedure:
To a solution of 310 mg (1 mmol) of N-(3-benzhydroxypropyl)piperazine in dry tetrahydrofuran (5 ml) was added a solution of 483 mg (1 mmol) of N-[5-(3,4-dimethoxyphenyl)-2,4-pentadienoyl]thiazolidine-2-thione in dry tetrahydrofuran (5 ml), and the mixture was allowed to react at room temperature for overnight under argon atmosphere. The reaction mixture was concentrated by evaporation under reduced pressure, diluted with chloroform and washed; in turn, with 2N aqueous solution of sodium hydroxide and water. The organic layer was dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (50:1), to give 470 mg (0.89 mmol) of N-[5-(3,4-dimethoxyphenyl)-2,4-pentadienoyl]-N'-(3-benzhydroxypropyl)piperazine. Spectrophotometric data of the product support the structure shown below. ##STR107##
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4].[Li+].[OH-]>C1COCC1.CO.O>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[C:17]([N:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:9]1[CH:8]=[C:7]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2])=[O:26]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)c1ccc(Cl)cc1Cl)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1sc(-c2ccccc2)cc1N(C(=O)c1ccc(Cl)cc1Cl)c1ccccc1
Reaction time: 1 h
Yield: 62.1 %

Procedure:
3-[(2,4-Dichloro-benzoyl)-phenyl-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (55 mg, 0.11 mmol) was dissolved in a mixture of THF-MeOH—H2O (3:2:1) (15 mL) and then 0.66 ml of LiOH 1N was added to it. After 60 min of stirring at room-temperature, solvents were removed and then partitioned between 15 ml of H2O, 4 ml of KHSO4 5% and 15 ml of EtOAc. The organic layer was separated and the aqueous phase was washed twice with ethyl acetate (2×10 mL). The combined ethyl acetate layer was dried (MgSO4), concentrated and the residue was purified by preparative chromatography (10% MeOH/CH2Cl2) to obtain 32 mg (60%) of 3-[(2,4-Dichloro-benzoyl)-phenyl-amino]-5-phenyl-thiophene-2-carboxylic acid. NMR 1H (DMSO, 400 MHz): Rotamer: 7.75 ppm (d, 1H, Haro); 7.68 ppm (2H, Haro); 7.53 ppm (d, Haro, minor rotamer); 7.51-7.23 ppm (m, 11H, Haro, minor rotamer); 7.17 ppm (Haro, minor rotamer).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[C:22]([O:26][C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C.[CH3:41][C:42]1[C:43]([N:58]2[CH2:67][CH2:66][C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[CH:59]2[CH3:68])=[N:44][C:45]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)=[N:46][C:47]=1[CH2:48]O>C(Cl)Cl>[CH3:41][C:42]1[C:43]([N:58]2[CH2:67][CH2:66][C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[CH:59]2[CH3:68])=[N:44][C:45]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)=[N:46][C:47]=1[CH2:48][O:32][C:31](=[O:33])[CH2:30][NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:28]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Cc1c(CO)nc(Nc2ccc(F)cc2)nc1N1CCc2ccccc2C1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(COC(=O)CNC(=O)OC(C)(C)C)nc(Nc2ccc(F)cc2)nc1N1CCc2ccccc2C1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-hydroxybenzotriazole(26.8 mg, 0.198 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(32.9 mg, 0.171 mmol), N-t-butoxycarbonylglycine(27.8 mg, 0.158 mmol) and triethylamine(23.9 μl 0.171 mmol) were added to a suspension of 5-methyl-6-hydroxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(50 mg, 0.132 mmol) in anhydrous methylene chloride(1 ml). The reaction mixture was stirred for 1 day at room temperature, washed with water. The separated organic layer was concentrated and the residual oil was purified by a silica gel column chromatography (dichloromethane/methanol 20/1) to give the titled compound.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:24]=[CH:23][C:14]3[N:15]([CH3:22])[C:16](=[O:21])[C:17]([F:20])([F:19])[O:18][C:13]=3[CH:12]=2)[CH2:6]1)=O.[CH3:25][NH2:26]>CO>[CH3:25][NH:26][C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:24]=[CH:23][C:14]3[N:15]([CH3:22])[C:16](=[O:21])[C:17]([F:20])([F:19])[O:18][C:13]=3[CH:12]=2)[CH2:6]1)=[O:2]
Reactant: CN
Reactant: COC(=O)[C@H]1CN(c2ccc3c(c2)OC(F)(F)C(=O)N3C)C(=O)O1
Solvent: CO
Product: CNC(=O)[C@H]1CN(c2ccc3c(c2)OC(F)(F)C(=O)N3C)C(=O)O1
Reaction time: 16 h
Yield: 50 %

Procedure:
To a stirred solution of (5R)-3-(2,2-Difluoro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-2-oxo-5-oxazolidinecarboxylic acid methyl ester (EXAMPLE 80, Step 3,50 mg, 0.14 mmol) in MeOH (1 mL) is added 2M MeNH2 in MeOH (2 mL, 4 mmol). The resulting mixture is stirred for 16 h at which time a precipitate forms. The mixture is heated until it becomes clear, and the product is allowed to crystallize at room temperature in the form of white needles. The crystals are separated, washed with ether and dried under high vacuum at 50° C. to give the title compound (25 mg, 50%), 1H NMR (300 MHz, DMSO) δ 8.38 (br d, 1H), 7.60 (d, 1H), 7.51-7.41 (m, 2H), 5.06 (dd, 1H), 4.29 (t, 1H), 4.03 (dd, 1H), 3.41 (s, 3H), 2.65 (d, 2H); MS for C14H13F2N3O5 m/z 342.5 (M+H)+.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:67])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[NH:63][N:64]=[C:65]([Cl:66])[C:52]3=[CH:51][CH:50]=4)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O>CO.O.Cl>[ClH:66].[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:48](=[O:67])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[NH:63][N:64]=[C:65]([Cl:66])[C:52]3=[CH:51][CH:50]=4)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5c(Cl)n[nH]c54)c3=O)cc2)CCC1
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5c(Cl)n[nH]c54)c3=O)cc2)CCC1
Yield: 72 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(3-chloro-6-oxo-8-phenyl-1,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (1.25 mL), water (3.75 mL) and 1 M HCl (0.15 mL) and chromatographed on a 2 g C18 cartridge {gradient 25 to 60% MeOH in water+1 M HCl (60 μL in each 5 mL of eluent)} to give the title compound (10.2 mg, 72%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.54 (br s, 3H), 7.82 (d, J=8.6 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.57-7.55 (m, 2H), 7.51-7.44 (m, 3H), 7.41-7.37 (m, 2H), 7.34 (d, J=8.3 Hz, 2H), 2.63-2.49 (m, 4H), 2.23-2.12 (m, 1H), 1.87-1.76 (m, 1H). LCMS (Method E): RT=3.51 min, [M+H]+=442/444.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=O)[C:7](=[O:13])[NH:8]2)([CH3:3])[CH3:2].[CH:15]1[C:20]([NH:21][NH2:22])=[CH:19][CH:18]=[C:17]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:16]=1.Cl>>[CH:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[N:22][NH:21][C:20]1[CH:19]=[CH:18][C:17]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:16][CH:15]=1)[C:7](=[O:13])[NH:8]2)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc2c1C(=O)C(=O)N2
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: CC(C)c1cccc2c1C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2
Yield: 73 %

Procedure:
The title compound was prepared from 4-isopropyl-1H-indole-2,3-dione (Krantz and Young, 1989, U.S. Pat. No. 4,873,232) and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G in 73% yield: 1H NMR (DMSO-d6): δ 1.30 (d, J=6.7 Hz, 6H), 3.82 (septet, J=6.7 Hz, 1H), 6.76 (d, J=7.8 Hz, 1H), 7.01 (d, J=7.8 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 7.24 (s, 2H), 7.48 (d, J=8.7 Hz, 2H), 7.79 (d, J=8.7 Hz, 2H), 11.10 (s, 1H), 13.05 (s, 1H); APCI-MS m/z 357 (M−1)−. Anal. Calcd for C17H18N4O3S: C, 56.97, H, 5.06; N, 15.63; S, 8.95. Found C, 56.88, H, 5.12; N, 15.73; S, 8.91.
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C:12](=[CH:13][C:14](=[O:22])[CH2:15][CH2:16]1)[N:11]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:10]3.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:42]=[N+:43]=[N-:44].[Na+]>ClCCl.CN(C1C=CN=CC=1)C.CN(C)C=O.C(OCC)(=O)C>[N:42]([CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C:12](=[CH:13][C:14](=[O:22])[CH2:15][CH2:16]1)[N:11]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:10]3)=[N+:43]=[N-:44]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2[C@@H]3CC[C@H](CO)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)C=C12
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H]2[C@@H]3CC[C@H](CN=[N+]=[N-])[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)C=C12
Temperature: 75 °C
Reaction time: 3 h

Procedure:
A solution of 17β-hydroxymethyl-6-t-butoxycarbonyl-6-azaandrost-4-en-3-one (2.03 g, 5.04 mmol) prepared in example 3, part 15, in dichloromethane (50 mL) is treated with triethylamine (0.88 mL, 6.3 mmol), DMAP (0.155 g, 1.27 mmol) and methanesulfonyl chloride (0.43 mL, 5.6 mmol). After 3 hrs, the reaction is diluted with dichloromethane (50 mL), washed with 1N HCl, saturated aqueous NaCl and dried over MgSO4. Concentration gives a white foam which is dissolved in dimethylformamide (50 mL), treated with sodium azide (0.94 g, 14.5 mmol) and heated to 75° C. for 16 hrs. The reaction is poured into ethyl acetate, washed with water (5×100 mL), dried over MgSO4, concentrated and chromatographed on silica gel (20% ethyl acetate/hexane) to give 17β-azidomethyl-6-t-butoxycarbonyl-6-azaandrost-4-en-3-one as a white foam of sufficient purity to carry on to the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:14]2[C:6](=[CH:7][C:8]3[CH:9]=[CH:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([CH3:16])([CH3:15])[CH2:4][CH2:3]1.[C:18]([C:22]1[CH:23]=[C:24](Br)[CH:25]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:27]=1)([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C.CN(C)C=O>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:18]([C:22]1[CH:23]=[C:24]([C:10]2[CH2:11][C:12]3[CH:13]=[C:14]4[C:2]([CH3:17])([CH3:1])[CH2:3][CH2:4][C:5]([CH3:16])([CH3:15])[C:6]4=[CH:7][C:8]=3[CH:9]=2)[CH:25]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:27]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)C=CC3
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)c1cc(C2=Cc3cc4c(cc3C2)C(C)(C)CCC4(C)C)cc(C(C)(C)C)c1
Temperature: 60 °C

Procedure:
A 100 mL round bottom flask fit with a magnetic stirrer was charged with 5,5,8,8-tetramethyl-5,6,7,8-tetrahydrobenz(f)indene (4.0 g, 0.018 mol), 3,5-di-t-butyl-bromobenzene (7.0 g, 0.026 mol), tri-o-toylphosphine (2.46 g, 0.0081 mol), triethylamine (4.3 mL, 0.31 mol), and dimethylformamide (60 mL, anhydrous, Aldrich). The solution was degassed, charged with palladium(II) acetate (00876 g, 0.0039 mol) and heated to 60° C. for 93 hours. At that point, after degassing ng again, additional palladium(II) acetate (0.876 g, 0.0039 mol) was added and heated to 60° C. for a total of 161 hours. The reaction mixture was dissolved in 200 mL diethyl ether, washed with 5% HCl (3×100 mL), sodium bicarbonate solution (3×100 mL), water (3×100 mL), and dried over anhydrous magnesium sulfate. The resulting crude oil weighed 11.0 g after rotary evaporation. This material was purified by column chromatography with silica/hexane followed by recrystallization from pentane to yield a fraction (0.8 g) enriched in the desired product. The mother liquid was resubmitted to the coupling conditions. A 50 mL round bottom flask was charged with the mother liquor (7.7 g), tri-o-toylphosphine (2.46 g, 0.0081 mol), triethylamine (4.3 mL, 0.31 mol), and dimethylformamide (35 mL, anhydrous, Aldrich). The solution was degassed, charged with palladium(II) acetate (0.876 g, 0.0039 mol) and heated to 60° C. During heating, periodically more reagents were added such that the totals charged were: tri-o-toylphosphine (3.46 g, 0.011 mol), 1,2-bis(diphenylphosphino)ethane (2.05 g, 0.0051 mol) triethylamine (5.3 mL, 0.38 mol), and dimethylformamide (35 mL, anhydrous, Aldrich), and palladium(II) acetate (3.27 g, 0.0145 mol). The reaction was cooled to room temperature, and worked up as above to yield 11.0 g of crude product. The paste was purified by column chromatography on silica/hexane three times, and the combined most enriched fractions gave 2.3 g which was then purified by preparative HPLC to yield 1.7 g of a semisolid paste. The paste was repeatedly recrystallized from methanol/acetone to yield the pure 2-(3,5-di-t-butylphenyl)-5,5,8,8 tetramethyl-5,6,7,8-tetrahydrobenz(f)indene (0.92 g). 1HNMR (CD2Cl2, 500 MHz) δ7.54 (d, J=1.5 Hz, 2H); 7.48 (s, 1H); 7.42 (s, 1H); 7.39 (s, 1H); 7.24 (s, 1H); 3.82 (s, 2H); 1.77 (s, 4H); 1.43 (s, 18H); 1.38 (s, 12H).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13](B(O)O)=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].Br[C:21]1[S:25][C:24]([CH3:26])=[N:23][C:22]=1[CH3:27].C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO.O>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:21]3[S:25][C:24]([CH3:26])=[N:23][C:22]=3[CH3:27])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: Cc1nc(C)c(Br)s1
Reactant: CCC(CC)c1cc(C)nn2c(B(O)O)c(C)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: CCC(CC)c1cc(C)nn2c(-c3sc(C)nc3C)c(C)nc12
Yield: 58.4 %

Procedure:
To a microwave pressure tube is added 0.340 g (1.30 mmol) of 8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine-3-yl boronic acid, 0.100 g (0.521 mmol) of 5-bromo-2,4-dimethylthiazole, 0.361 g (0.313 mmol) of Pd(PPh3)4, 0.650 mL (1.30 mmol) of 2 M aqueous Na2CO3, and 2 mL 7:3:2 DME:H2O:EtOH, and the mixture is heated at 160° C. for 40 min. Reaction is checked by MS which indicates product present. The reaction mixture is partitioned between 75 mL of ethyl acetate and 75 mL of water. The layers are separated and the aqueous is extracted 3×50 mL of ethyl acetate, dried (MgSO4), and concentrated under vacuum. The crude mixture is purified by chromatography using hexanes/ethyl acetate as a solvent system. The product containing fractions are combined to obtain 0.100 g of the product, 58% yield. MS, ES+=329.2 (M+1); 1H-NMR (DMSO-d6)=6.974 (s, 1H); 3.085-3.052 (m, 1H); 2.665 (s, 3H); 2.438 (s, 3H); 2.290 (s, 3H); 2.147 (s, 3H); 1.849-1.727 (m, 4H); 0.776-0.738 (m, 6H) ppm.
Reaction SMILES: O.[PH2]([O-])=O.[Na+].C=C.[NH4+].[NH4+].[O-]S(OOS([O-])(=O)=O)(=O)=O.[Al:20].[Al+3].[CH2:22]([P:24](CC)(=[O:26])[O-:25])[CH3:23].[CH2:29]([P:31](CC)(=[O:33])[O-:32])[CH3:30].[CH2:36]([P:38](CC)(=[O:40])[O-:39])[CH3:37]>O>[Al+3:20].[CH2:22]([P:24]([O-:26])[O-:25])[CH3:23].[CH2:29]([P:31]([O-:33])[O-:32])[CH3:30].[CH2:36]([P:38]([O-:40])[O-:39])[CH3:37].[Al+3:20]
Reactant: CCP(=O)([O-])CC
Reactant: [Al]
Agent: C=C
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=[PH2][O-]
Solvent: O
Product: CCP([O-])[O-]
Temperature: 100 °C
Yield: 96.3 %

Procedure:
1500 g (14 mol) of sodium hypophosphite monohydrate are dissolved in 7.5 kg of water and initially charged in a 16 l steel-enamel jacketed pressure reactor. After heating the reaction mixture to 100° C., a reducing valve set to 20 bar is used to introduce ethylene into the reactor up to saturation. While stirring constantly at an ethylene pressure of 20 bar and a temperature of 100-110° C., a solution of 32 g (1 mol %) of ammonium peroxodisulfate in 300 g of water is metered in homogeneously. At a conversion of ethylene of 90%, the metered addition of ammonium peroxodisulfate is stopped and the reactor is decompressed. After cooling to about 90° C., 3000 g (4.67 mol of aluminum) of a 46% aqueous solution of Al2(SO4)3.14H2O is added within 60 minutes. Subsequently, the resulting solid is filtered off, washed with 2 l of hot water and dried at 130° C. under reduced pressure. The resulting mixture comprises diethylphosphinic acid aluminum(III) salt and ethylphosphonous acid aluminum(III) salt in a ratio of 87.3% by weight of diethylphosphinic acid aluminum(III) salt and 12.7% by weight of ethylphosphonous acid aluminum(III) salt (96.3% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[N:11]1.[CH3:26]C(C)([O-])C.[K+].CI>CS(C)=O.CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:26])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=2[F:23])=[N:11]1
Reactant: O=C(Nc1ccn(Cc2ccc(O)cc2Cl)n1)c1c(F)cccc1F
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: CI
Solvent: CS(C)=O
Product: COc1ccc(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{1-[(2-chloro-4-hydroxyphenyl)methyl]-1H-pyrazol-3-yl}-2,6-difluorobenzamide (for a preparation see Example 31)(30 mg, 0.082 mmol) in DMSO (0.5 ml) was added potassium t-butoxide (9.6 mg, 0.086 mmol) and then methyl iodide (6 μl, 0.096 mmol, Aldrich). The solution was stirred at ambient temperature overnight. The solution was diluted with methanol (0.5 ml) and purified by MDAP on Sunfire C18 column using Acetonitrile-Water with a Formic acid modifier (Method B). The solvent was evaporated in vacuo to give the title compound as a colourless gum (7.3 mg); LCMS: (System 4) MH+=378, tRET=2.85 min.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([C:17](O)=[O:18])[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:50][N:51]1[CH2:56][CH2:55][CH:54]([NH2:57])[CH2:53][CH2:52]1>C1COCC1.CN(C=O)C>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:7]1[C:8]2[C:9]3[C:14](=[CH:13][C:12]([C:17]([NH:57][CH:54]4[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]4)=[O:18])=[CH:11][CH:10]=3)[NH:15][C:16]=2[C:4]([C:1]([NH2:2])=[O:3])=[CH:5][CH:6]=1
Reactant: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(C(=O)O)ccc12
Reactant: CN1CCC(N)CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(-c4ccccc4F)c23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
A mixture of 8-carbamoyl-5-(2-fluorophenyl)-9H-carbazole-2-carboxylic acid (Example 23-2, 30 mg, 0.086 mmol), EDC (23.11 mg, 0.121 mmol), HOBT (18.46 mg, 0.121 mmol), DIEA (30 μL, 0.172 mmol), and 1-methylpiperidin-4-amine (9.83 mg, 0.086 mmol) in THF and DMF (4:1, 2 mL) was stirred at rt overnight. The mixture was concentrated and purified by preparative HPLC. The isolated product was partitioned between DCM and NaHCO3 (aq). The organic phase was dried and concentrated to provide 4-(2-fluorophenyl)-N7-(1-methylpiperidin-4-yl)-9H-carbazole-1,7-dicarboxamide as a white solid (25 mg, 62%). 1H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1 H) 8.24 (br. s., 1 H) 8.20 (s, 1 H) 8.13 (d, J=7.69 Hz, 1 H) 8.05 (d, J=7.91 Hz, 1 H) 7.52-7.68 (m, 3 H) 7.33-7.48 (m, 3 H) 7.13 (d, J=7.69 Hz, 1 H) 7.05 (d, J=8.35 Hz, 1 H) 3.64-3.80 (m, 1 H) 2.69-2.79 (m, 2 H) 1.87-2.00 (m, 2 H) 1.70-1.80 (m, 2 H) 1.48-1.65 (m, 2 H). Mass spectrum m/z 445.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[NH:11][CH2:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:5])[CH3:2].B.N1C=CC=CC=1.C(OC([C@@H]1CCC[C@H]1NCCC(C)(C)C)=O)C>C(O)(=O)C>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[NH:11][CH2:12][CH2:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(NCCC(C)(C)C)CCC1
Agent: B
Agent: CCOC(=O)[C@@H]1CCC[C@H]1NCCC(C)(C)C
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H]1CCC[C@@H]1NCCC(C)(C)C
Reaction time: 0.25 h
Yield: 7.3 %

Procedure:
To a solution of 2-(3,3-dimethylbutylamino)-cyclopent-1-enecarboxylic acid ethyl ester (5.59 g, 23.4 mmol) in acetic acid (70 mL) was added a 8.0 M solution of borane in pyridine (3.2 mL, 25.6 mmol) at 25° C. After stirring for 15 min, the reaction mixture was concentrated in vacuo. The crude material was triturated with 1.0 M aqueous hydrochloric acid solution (25 mL) and stirred for 0.5 h (until the gas evolution ceased). The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude material was purified by flash column chromatography (Teledyne Isco RediSep Flash Column; 0-10% methanol in dichloromethane) to afford cis-2-(3,3-dimethylbutylamino)-cyclopentanecarboxylic acid ethyl ester as a yellowish oil (0.40 g, 1.7 mmol, 7%) and trans-2-(3,3-dimethylbutylamino)-cyclopentanecarboxylic acid ethyl ester and an off-white solid (2.37 g, 9.8 mmol, 42%). cis-2-(3,3-Dimethylbutylamino)-cyclopentanecarboxylic acid ethyl ester: 1H NMR (400 MHz, CDCl3) δ 0.91 (9H, s), 1.28 (3H, t, J=7.0 Hz), 1.35-1.50 (2H, m), 1.56-1.73 (2H, m), 1.80-2.03 (4H, m), 2.60-2.75 (2H, m), 2.98-3.02 (1H, m), 3.35 (1H, q, J=7.4 Hz), 4.15 (2H, q, J=6.9 Hz), 6.38 (1H, s). trans-2-(3,3-Dimethylbutylamino)-cyclopentanecarboxylic acid ethyl ester: 1H NMR (400 MHz, CDCl3) δ 0.94 (9H, s), 1.29 (3H, t, J=7.0 Hz), 1.66-2.01 (6H, m), 2.11-2.27 (2H, m), 2.86 (2H, t, J=8.6 Hz), 3.10 (1H, q, J=7.8 Hz), 3.68 (1H, q, J=7.0 Hz), 4.18 (2H, q, J=7.0 Hz). LC-MS (ESI) calcd for C14H27NO2 241.20, found 242.4 [M+H+].