Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:18])[C:7](=[O:17])[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][C:11]([OH:16])=[CH:10][CH:9]=3.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:28][CH:29]1[CH2:31][CH2:30]1>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:18])[C:7](=[O:17])[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][C:11]([O:16][CH2:28][CH:29]1[CH2:31][CH2:30]1)=[CH:10][CH:9]=3
Reactant: BrCC1CC1
Reactant: O=C1C(=O)c2ccc(Br)cc2-c2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1C(=O)c2ccc(OCC3CC3)cc2-c2cc(Br)ccc21

Procedure:
A solution of 3-bromo-6-hydroxyphenanthrene-9,10-dione from Step 4 in acetone was treated with excess potassium carbonate, potassium iodide and (bromomethyl)cyclopropane. The mixture was heated at reflux overnight, followed by standard workup to yield 3-bromo-6-(cyclopropylmethoxy)phenanthrene-9,10-dione.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[S:6]1(=[O:24])=[O:23].[CH3:25][NH2:26].Cl>>[ClH:1].[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:26][CH3:25])[S:6]2(=[O:24])=[O:23])=[CH:16][CH:17]=1
Reactant: CN
Reactant: COc1ccc(N2c3ccccc3CN(CCCCl)S2(=O)=O)cc1
Agent: Cl
Product: CNCCCN1Cc2ccccc2N(c2ccc(OC)cc2)S1(=O)=O

Procedure:
In an analogous manner to Example 1, step 8, 3-(3-chloropropyl)-1-(4-methoxyphenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (105 mg) was reacted with methylamine and then treated with HCl to provide 3-[1-(4-methoxyphenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine hydrochloride (32 mg):
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=1.Cl[CH2:13][C:14]1[C:15]2[N:16]([CH:20]=[CH:21][N:22]=2)[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:22]1[CH:21]=[CH:20][N:16]2[CH:17]=[CH:18][CH:19]=[C:14]([CH2:13][O:1][C:2]3[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=3)[C:15]=12
Reactant: COc1cc(C=O)c(O)cn1
Reactant: ClCc1cccn2ccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(OCc2cccn3ccnc23)cn1
Temperature: 125 °C
Yield: 37.6 %

Procedure:
A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (723.6 mg, 4.7 mmol), 8-(chloromethyl)-imidazol[1,2-a]pyridine (785 mg, 4.7 mmol), and K2CO3 (1.9 g, 14.1 mmol) in DMF (20 mL) was heated at microwave reactor at 125° C. for 15 min. The mixture was filtered and concentrated. The residue was purified on silica gel (50-100% EtOAc in hexanes) to give 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-methoxyisonicotinaldehyde (500 mg, 38%) as an off-white solid. 1H NMR (400 MHz; DMSO) δ=10.37 (s, 1H), 8.58 (d, 1H), 8.39 (s, 1H), 8.02 (s, 1H), 7.61 (s, 1H), 7.44 (d, 1H), 6.98 (s, 1H), 6.93 (t, 1H), 5.61 (s, 2H), 3.84 (s, 3H). LRMS (M+H+) m/z 284.0.
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[CH3:12][C:13]1([CH3:23])[C:18]([CH3:19])=[CH:17][CH2:16][C@H:15]([CH3:20])[C@@H:14]1[CH2:21][OH:22]>C(Cl)Cl>[CH3:23][C:13]1([CH3:12])[C:18]([CH3:19])=[CH:17][CH2:16][CH:15]([CH3:20])[CH:14]1[CH:21]=[O:22]
Reactant: CC1=CC[C@H](C)[C@H](CO)C1(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC1=CCC(C)C(C=O)C1(C)C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
Prepared according to the method described, starting from 15.0 g (70 mmol) of PCC in 150 ml of CH2Cl2 and 8.38 g (50 mmol) of cis-2,2,3,6-tetramethyl-3-cyclohexene-1-methanol, obtained as in example 3b., in 50 ml of CH2Cl2. After stirring for 1 h, the reaction mixture was treated as described above to yield 6.77 g of the desired aldehyde in the form of a yellow oil (2 isomers, cis/trans~9:1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[C:4]([F:11])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[NH2:26][C:27]1[C:35]([NH2:36])=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([NH2:31])=[O:30]>N1C=CC=CC=1.CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[NH:36][C:35]3[CH:34]=[CH:33][CH:32]=[C:28]([C:29]([NH2:31])=[O:30])[C:27]=3[N:26]=2)=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: NC(=O)c1cccc(N)c1N
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: NC(=O)c1cccc2[nH]c(-c3ccc(Br)cc3F)nc12
Temperature: 45 °C
Reaction time: 1 h

Procedure:
4-Bromo-2-fluorobenzoic acid (5 g) in a mixture of pyridine (50 mL) and DMF (50 mL) at 45° C. was treated with CDI (0.856 g), stirred at 45° C. for 1 hour, treated with 2,3-diaminobenzamide dihydrochloride (5.1 g), stirred at ambient temperature for 18 hours and concentrated. The concentrate was dissolved in acetic acid (100 mL), heated at 70° C. for 1 hour and concentrated. The concentrate was partitioned between ethyl acetate and sodium bicarbonate solution and the organic phase was isolated, washed with brine and concentrated. The concentrate was flash chromatographed on silica gel with ethyl acetate.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10](Cl)[CH:11]=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:14]=[C:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19]>>[Si:1]([O:8][CH2:9][C@H:10]1[C@@H:17]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=[C:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:14][C:11]1=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC(Cl)C=O
Reactant: COC(=O)/C=C/C(=O)c1ccccc1
Product: COC(=O)[C@H]1C=C(c2ccccc2)OC(=O)[C@H]1CO[Si](C)(C)C(C)(C)C
Yield: 80 %

Procedure:
Prepared according to the general procedure from 3-(tert-butyldimethylsilyloxy)-2-chloropropanal and (E)-methyl 4-oxo-4-phenylbut-2-enoate using 0.5 mol % 1 as the catalyst in 80% yield as a 3:1 mixture of diastereomers. The diastereomers were separated by silica gel chromatography (15:1 hexanes/EtOAc) and characterized separately. [α]D20 (c 1.07, CHCl3)=+133.6; 1H NMR (400 MHz, CDCl3) δ 7.65-7.62 (m, 2H), 7.40-7.37 (m, 3H), 5.94 (d, 1H, J=7.1 Hz), 4.26 (dd, 1H, J=10.6, 5.7 Hz), 3.88 (t, 1H, J=10.1 Hz), 3.76 (dd, 1H, J=13.7, 7.4 Hz), 3.72 (s, 3H), 3.08-3.02 (m, 1H), 0.89 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.9, 167.7, 152.5, 131.9, 129.8, 128.8, 125.0, 98.1, 59.7, 52.6, 42.5, 38.7, 25.9, 18.4, −5.4, −5.6; IR (thin film) ν 3062, 2953, 2929, 2886, 2857, 1778, 1739, 1254, 1197, 1176 cm−1; HRMS (EI) calcd for C20H25O5Si [M]+ 376.1706, found 376.1697; 97% ee (3R,4S)-isomer as determined by HPLC (AD-H, 100:1 hexanes/i-PrOH), tr (3R,4S)=21.8 min, tr (3S,4R)=15.2 min.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([OH:13])[CH:10]=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.C1(C2N=C[C:28]([OH:31])=[N:29]C=2)C=CC=CC=1.ClC1C=NC=C(C2C=CC=CC=2)N=1.ClC1C=NC(C2C=CC=CC=2)=CN=1.CC(C1C=NC=C(C2C=CC=CC=2)N=1)(C(OCC)=O)C(OCC)=O.CC(C1C=NC(C2C=CC=CC=2)=CN=1)(C(OCC)=O)C(OCC)=O.CC(C1C=NC=C(C2C=CC=CC=2)N=1)C(OCC)=O.CC(C1C=NC(C2C=CC=CC=2)=CN=1)C(OCC)=O.CC(C1C=NC=C(C2C=CC=CC=2)N=1)C(O)=O.CC(C1C=NC=C(C2C=CC=CC=2)N=1)C(N)=O>>[OH:13][C:11]1[C:10]([C:28]([NH2:29])=[O:31])=[N:9][CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:12]=1
Reactant: Oc1cnc(-c2ccccc2)cn1
Reactant: Oc1cncc(-c2ccccc2)n1
Agent: CC(C(=O)O)c1cncc(-c2ccccc2)n1
Agent: CC(C(N)=O)c1cncc(-c2ccccc2)n1
Agent: CCOC(=O)C(C)(C(=O)OCC)c1cnc(-c2ccccc2)cn1
Product: NC(=O)c1ncc(-c2ccccc2)nc1O

Procedure:
3-Hydroxy-5-phenylpyrazine-2-carboxamide is prepared by the method of Dick, Wood and Logan, J. Chem. Soc., 2131 (1956). The carboxamide is converted to 6-phenylpyrazinol by the method of Jezo and Luzak, Chem. Zvest., 22, 190 (1968), using 80 percent sulfuric acid at 180° C. Using the procedure of Example III and replacing 5-phenylpyrazinol with an equivalent amount of 6-phenylpyrazinol, the product obtained is 2-chloro-6-phenylpyrazine. Using the procedure of Example V and replacing 2-chloro-5-phenylpyrazine with an equivalent amount of 2-chloro-6-phenylpyrazine, the product obtained is diethyl α-methyl-6-phenylpyrazinylmalonate. Using the procedure of Example VI and replacing diethyl α-methyl-5-phenylpyrazinylmalonate with an equivalent amount of diethyl α-methyl-6-phenylpyrazinylmalonate, the product obtained is ethyl α-methyl-6-phenylpyrazineacetate. Using the procedure of Example IX and replacing ethyl α-methyl-5-phenylpyrazineacetate with an equivalent amount of ethyl α-methyl-6-phenylpyrazineacetate, the product obtained is α-methyl-6-phenylpyrazineacetic acid. Using the procedure of Example XI and replacing ethyl α-methyl-5 -phenylpyrazineacetate with an equivalent amount of ethyl α-methyl-6-phenylpyrazineacetate, the product obtained is α-methyl-6-phenylpyrazineacetamide.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:20][N:14]4[C:15](=[O:19])[CH2:16][NH:17][CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>ClCCl>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:20][N:14]4[C:15](=[O:19])[CH2:16][N:17]([C:34](=[O:35])[C:33]5[CH:37]=[CH:38][C:30]([C:29]([F:28])([F:39])[F:40])=[CH:31][CH:32]=5)[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: O=C1CNC[C@@H]2C[C@@H](Oc3cnc(C4CC4)cn3)CN12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(C(F)(F)F)cc1)N1CC(=O)N2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.9 %

Procedure:
To a solution of the product from Example 174G (100 mg, 0.365 mmol) in dichloromethane (2 mL) were added triethylamine (50.8 μL, 0.365 mmol) followed by 4-(trifluoromethyl)benzoyl chloride (59.7 μL, 0.401 mmol). The mixture was stirred at ambient temperature for 18 hours, and then partitioned between water and dichloromethane. The organic extract was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on a 12 g silica gel column eluting with 5% ethyl acetate/hexanes for 3 minutes and then a gradient to 100% ethyl acetate over 20 minutes to give the title compound (34 mg, 20.9%). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.16 (t, J=8.3 Hz, 2H), 7.83 (d, J=8.2 Hz, 2H), 7.73-7.60 (m, 2H), 5.62-5.41 (m, 1H), 4.85-4.46 (m, 1H), 4.10-3.61 (m, 4H), 3.50-3.34 (m, 1H), 3.24-2.71 (m, 1H), 2.44-1.65 (m, 3H), 1.05-0.90 (m, 2H), 0.87-0.73 (m, 2H); MS (ESI) m/z 447 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:23]=[CH:22][C:8]2[CH:9]=[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:11]([C:13]([F:16])([F:15])[F:14])[O:12][C:7]=2[CH:6]=1)([CH3:4])[CH3:3].C(O)(=O)C.O.[Cl:29]Cl>C(OCC)(=O)C.[Zn]>[Cl:29][C:23]1[C:5]([C:2]([CH3:3])([CH3:1])[CH3:4])=[CH:6][C:7]2[O:12][CH:11]([C:13]([F:15])([F:16])[F:14])[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:9][C:8]=2[CH:22]=1
Reactant: ClCl
Reactant: CCOC(=O)C1=Cc2ccc(C(C)(C)C)cc2OC1C(F)(F)F
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C1=Cc2cc(Cl)c(C(C)(C)C)cc2OC1C(F)(F)F
Temperature: 15 °C
Reaction time: 2 h
Yield: 106.6 %

Procedure:
A one liter three-neck flask equipped with mechanical stirrer and gas inlet tube was charged with the ester (Step 2) (100 g, 0.3 mole) and acetic acid (300 mL). While cooling (water bath) the reaction mixture, chlorine gas (37.6 g, 0.53 mole) was added which caused the temperature to rise to 48° C. After stirring for two hours, the reaction was cooled in an ice-water bath to 15° C. Zinc powder (19.5 g, 0.3 mole) was added in one portion which caused the temperature to rise to 72° C. After cooling to room temperature additional zinc powder (5.0 g, 0.08 mole) was added and the mixture was stirred for 0.5 hour longer. The crude mixture was filtered through diatomaceous earth and was concentrated in vacuo yielding an oil. The oil was dissolved in ethyl acetate (700 mL) washed with brine-water (1:1, 1 L) and brine (0.5 L). The resulting aqueous phase was extracted with ethyl acetate (700 mL). This ethyl acetate phase was washed with brine-water (1:1, 1 L) and brine (0.5 L). The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo yielding the title compound as a yellow oil (116 g, 106%). This material, which contained some entrained ethyl acetate, was of suitable purity to be used in subsequent steps without further purification.
Reaction SMILES: C1(S([N:10]2[C:14]3=[CH:15][N:16]=[CH:17][CH:18]=[C:13]3[C:12]([C:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25]([C:28]5[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=5)[CH:26]=4)[NH:21][CH:20]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)C(F)(F)F.C1COCC1>[CH3:33][N:31]1[CH:32]=[C:28]([C:25]2[CH:26]=[C:27]3[C:19]([C:12]4[C:13]5[C:14](=[CH:15][N:16]=[CH:17][CH:18]=5)[NH:10][CH:11]=4)=[CH:20][NH:21][C:22]3=[N:23][CH:24]=2)[CH:29]=[N:30]1
Reactant: Cn1cc(-c2cnc3[nH]cc(-c4cn(S(=O)(=O)c5ccccc5)c5cnccc45)c3c2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: OCC(F)(F)F
Product: Cn1cc(-c2cnc3[nH]cc(-c4c[nH]c5cnccc45)c3c2)cn1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
A suspension of 112 mg (0.25 mmol) of 1-benzenesulfonyl-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-1H-pyrrolo[2,3-c]pyridine (“A14”) and 261 mg (0.74 mmol) of caesium carbonate in 1 ml of trifluoroethanol and 2 ml of THF is stirred at 65° C. for 18 hours. The reaction mixture is evaporated, and the residue is chromatographed on a silica-gel column with dichloromethane/methanol as eluent: 3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-1H-pyrrolo[2,3-c]pyridine as colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:18][CH2:19][CH2:20][CH3:21])[C:15](O)=[O:16])[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH:25]1[C:29]([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)=[N:28][N:27]=[N:26]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:18][CH2:19][CH2:20][CH3:21])[C:15]([NH:34][C:33]3[CH:35]=[CH:36][C:30]([C:29]4[NH:28][N:27]=[N:26][N:25]=4)=[CH:31][CH:32]=3)=[O:16])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CCCCC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: Nc1ccc(-c2nnn[nH]2)cc1
Product: CCCCC(C(=O)Nc1ccc(-c2nnn[nH]2)cc1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
95 mg (purity 78%, 0.22 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]hexanoic acid (racemate) (Example 5.1C) and 42 mg (0.26 mmol) of 4-(1H-tetrazol-5-yl)aniline were reacted according to General Method 1. Yield: 32 mg (30% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:21])[CH2:12][NH:13][C:14]2[C:15](=[O:20])[NH:16][N:17]=[CH:18][CH:19]=2)[CH2:7][CH2:6]1.C([O-])([O-])=O.[K+].[K+].[F:36][C:37]([F:43])([F:42])[CH2:38][CH2:39][CH2:40]I>CN(C=O)C>[Cl:1][C:2]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:21])[CH2:12][NH:13][C:14]2[C:15](=[O:20])[N:16]([CH2:40][CH2:39][CH2:38][C:37]([F:43])([F:42])[F:36])[N:17]=[CH:18][CH:19]=2)[CH2:7][CH2:6]1
Reactant: O=C(CNc1ccn[nH]c1=O)N1CCC(Oc2cc(C(F)(F)F)ccc2Cl)CC1
Reactant: FC(F)(F)CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CNc1ccnn(CCCC(F)(F)F)c1=O)N1CCC(Oc2cc(C(F)(F)F)ccc2Cl)CC1
Yield: 67 %

Procedure:
Compound 45 is prepared following synthesis method 6: 0.3 g (0.7 mmol) of intermediate 7b are placed in 10 mL DMF in the presence of 0.13 g (0.94 mmol) K2CO3 then 0.222 g (0.90 mmol) of 1,1,1-trifluoro-4-iodo-butane and agitated at 80° C. for 32 h. After concentrating to dryness, the residue is solubilized in water and extracted with AcOEt. The organic phases are washed in brine, dried over Na2SO4 then concentrated to dryness. The residue is purified by silica gel flash chromatography (gradient CH2Cl2-MeOH: 100:0 to 99:1 for 30 nm). 0.250 g of compound 45 are collected (yield: 67%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22])#[N:14]>>[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:23])=[O:22])#[N:14]
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccccc2C#N)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2-cyanobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (24.6 mg) with purity >90%. MS (pos) m/z 352.2.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([NH:36]N)=[CH:28][CH:27]=1>>[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([N:36]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:28][CH:27]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: NNc1ccnc2ccccc12
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1ccnc2ccccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and quinolin-4-yl-hydrazine according to the method described for example 91. MS: M=450.2 (M+H)+
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][CH:44]=1)[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([N:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[CH:32]=1>CN(C)C=O.CN(C)C(=O)C>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:24]=[C:23]([NH:22][C:8]([C:7]5[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][CH:6]=5)=[O:10])[CH:44]=[CH:43][CH:42]=4)=[CH:32][N:31]3[N:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: CCn1nccc1C(=O)O
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCn1nccc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Yield: 82.9 %

Procedure:
In the same manner as in Example 18-4 and using 1-ethyl-1H-pyrazole-5-carboxylic acid (269 mg, 1.92 mmol), tetrahydrofuran (7 mL), oxalyl chloride (169 μL, 1.94 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.646 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (231 mg, 83%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[F:6][C:7]1[C:8]2[O:33][N:32]=[C:31]([C:34]3[CH:39]=[CH:38][N:37]=[C:36](S(C)(=O)=O)[N:35]=3)[C:9]=2[CH:10]=[C:11]2[C:24]=1[N:23]1[CH2:25][C@@H:26]([CH3:30])[O:27][C@@H:28]([CH3:29])[C@@H:22]1[C:13]1([C:18](=[O:19])[NH:17][C:16](=[O:20])[NH:15][C:14]1=[O:21])[CH2:12]2.CS(C)=O.O(C(N)C)C>C1COCC1>[F:6][C:7]1[C:8]2[O:33][N:32]=[C:31]([C:34]3[CH:39]=[CH:38][N:37]=[C:36]([NH:5][CH2:4][CH2:3][O:2][CH3:1])[N:35]=3)[C:9]=2[CH:10]=[C:11]2[C:24]=1[N:23]1[CH2:25][C@@H:26]([CH3:30])[O:27][C@@H:28]([CH3:29])[C@@H:22]1[C:13]1([C:18](=[O:19])[NH:17][C:16](=[O:20])[NH:15][C:14]1=[O:21])[CH2:12]2
Reactant: COCCN
Reactant: C[C@@H]1CN2c3c(cc4c(-c5ccnc(S(C)(=O)=O)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Agent: COC(C)N
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COCCNc1nccc(-c2noc3c(F)c4c(cc23)CC2(C(=O)NC(=O)NC2=O)[C@H]2[C@H](C)O[C@H](C)CN42)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
2-Methoxyethanamine (8.70 μL, 0.10 mmol) was added o a solution of (2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-(2-(methylsulfonyl)pyrimidin-4-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3H)-trione (Example 169, 50 mg, 0.09 mmol) in THF (5 mL), and the mixture was stirred at room temperature for 3 hours, DMSO (1 ml) was added followed by the addition of 2 more equivalence of methoxylethanamine, the mixture was stirred at room temperature for over night. The crude was concentrated and purified by reverse phase silica gel column chromatography (20-70% MeCN in water gradient, 0.1% TFA) to give 37 mg of product.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([C:9](=[N:11][OH:12])[NH2:10])=[N:6][CH:5]=1)([O-:3])=[O:2].[Cl:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19](Cl)=O>>[Cl:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]1[O:12][N:11]=[C:9]([C:7]2[S:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][N:6]=2)[N:10]=1
Reactant: NC(=NO)c1ncc([N+](=O)[O-])s1
Reactant: O=C(Cl)c1sccc1Cl
Product: O=[N+]([O-])c1cnc(-c2noc(-c3sccc3Cl)n2)s1

Procedure:
The title compound was prepared from 5-nitro-thiazole-2-amidoxime (17.2 mg, 0.0914 mmol) and 3-chloro-thiophene-2-carbonyl chloride (16.4 mg, 0.0905 mmol) similar to Example 16, and yielded 6.7 mg (23%) of yellow solid. 1H NMR (CDCl3): 8.74 (s, 11H), 7.70 (d, J=5.22 Hz, 1H), 7.18 (d, J=5.22 Hz, 1H).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:25][CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]2)[CH2:24][CH2:23][CH2:22][CH2:21]1.C(OCC)(=O)C.C(OCC)C>ClCCl.CO>[N:20]1([CH2:25][CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:30]2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C(CCN1CCCC1)CC1CCCNC1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: O=C1Nc2cccnc2N(C(=O)N2CCCC(CCCCN3CCCC3)C2)c2ccccc21
Yield: 50 %

Procedure:
Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 3-[4-(1-pyrrolidinyl)butyl]piperidine in a yield of 50% of theory. Colourless crystals, m.p. 153°-156° C. (ethyl acetate/diethylether 1/1, v/v), Rf 0.25 (Merck DC ready made TLC plates, silica gel 60 F254 ; eluant: dichloromethane/methanol/conc. ammonia 90/10/1, v/v/v).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][N:6]=[CH:5]2.[CH3:12]C([O-])(C)C.[K+].CI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[N:7]([CH3:12])[N:6]=[CH:5]2
Reactant: Fc1cc2[nH]ncc2cc1Br
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ncc2cc(Br)c(F)cc21
Reaction time: 0.67 h
Yield: 43.7 %

Procedure:
To a solution of 5-bromo-6-fluoro-1H-indazole (4 g, 18.60 mmol) in DMF (20 mL) was added potassium 2-methylpropan-2-olate (2.087 g, 18.60 mmol). The resulting mixture was stirred for 40 min. CH3I (3.17 g, 22.32 mmol) was added dropwise. After stirring overnight, the reaction mixture was quenched with NH4Cl (aq), extracted with EtOAc, washed with NH4Cl (aq), dried over Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified with silica gel column chromatography with gradient hexanes:EtOAc to give 5-bromo-6-fluoro-1-methyl-1H-indazole (1.86 g, 42%) as light yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([CH3:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[C:24]([O:25][CH3:26])=[CH:23][C:22]([N:27]2[CH2:32][CH2:31][CH:30]([N:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]2)=[C:21]([CH3:36])[CH:20]=1>>[CH3:35][N:33]([CH3:34])[CH:30]1[CH2:29][CH2:28][N:27]([C:22]2[C:21]([CH3:36])=[CH:20][C:19]([NH:18][C:2]3[N:7]=[C:6]([C:8]4[C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[NH:10][CH:9]=4)[C:5]([CH3:17])=[CH:4][N:3]=3)=[C:24]([O:25][CH3:26])[CH:23]=2)[CH2:32][CH2:31]1
Reactant: Cc1cnc(Cl)nc1-c1c[nH]c2ccccc12
Reactant: COc1cc(N2CCC(N(C)C)CC2)c(C)cc1N
Product: COc1cc(N2CCC(N(C)C)CC2)c(C)cc1Nc1ncc(C)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2-chloro-5-methylpyrimidin-4-yl)-1H-indole (INTERMEDIATE 1) and 1-(4-amino-5-methoxy-2-methylphenyl)-N,N-dimethylpiperidin-4-amine (INTERMEDIATE 30).