Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]#[C:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22][CH2:21]3)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(OC(=O)NC1(C#CC2C=CC(S(=O)(=O)NC3CCC4CC3C4(C)C)=CC=2)COC(C)(C)OC1)(C)(C)C>>[C:31]([O:30][C:29](=[O:35])[NH:28][C:20]1([CH2:19][CH2:18][C:15]2[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][CH2:9][NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][CH:14]=2)[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22][CH2:21]1)([CH3:32])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)NC1(C#Cc2ccc(C#CCNc3ccc(F)cc3)cc2)COC(C)(C)OC1
Agent: CC(C)(C)OC(=O)NC1(C#Cc2ccc(S(=O)(=O)NC3CCC4CC3C4(C)C)cc2)COC(C)(C)OC1
Product: CC(C)(C)OC(=O)NC1(CCc2ccc(CCCNc3ccc(F)cc3)cc2)COC(C)(C)OC1
Yield: 94 %

Procedure:
When the product of Step B was substituted for tert-butyl-5-((4-(N-(6,6-dimethylbicyclo[3.1.1]heptan-2-yl)sulfamoyl)phenyl-)ethynyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 19, Step C, the similar process afforded the title compound in 94% yield, as creamy gum. 1H-NMR (CDCl3) 1.42 (s, 3H); 1.44 (s, 3H); 1.46 (s, 9H); 1.87-1.96 (m, 4H); 2.5-2.56 (m, 2H); 2.67 (tr, 2H, J=7.32 Hz); 3.04 (tr, 2H, J=7.05 Hz); 3.86 (d, 2H, J=11.8 Hz); 3.88 (d, 2H, J=11.7 Hz); 4.9 (s, 1H); 6.45-6.50 (m, 2H); 6.82-6.88 (m, 2H); 7.09 (s, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]1[CH:13]=[N:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)=[O:5])[CH3:2].[NH:32]1[CH:36]=[CH:35][CH:34]=[N:33]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:1]([O:3][C:4]([C:6]1([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]1[CH:13]=[N:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:32]3[CH:36]=[CH:35][CH:34]=[N:33]3)=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CCC(=O)N1c1ccc(Oc2ccc(CBr)cc2)nc1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)OCC)CCC(=O)N1c1ccc(Oc2ccc(Cn3cccn3)cc2)nc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 1-[6-(4-bromomethyl-phenoxy)-pyridin-3-yl]-5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.2 g, 0.4 mmol) in 0.8 mL of dimethylformamide was added pyrazole (0.056 g, 0.82 mmol) and potassium carbonate (0.11 g, 0.82 mmol). After stirring for 24 hours at 50° C., the mixture was diluted with water, extracted three times with ethyl acetate, and the combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo, affording the crude product as a colorless syrup that was used directly in the next step. MS (APCl, m/z): 479.2 [M+H]+.
Reaction SMILES: I[CH2:2][C:3]([NH2:5])=[O:4].Cl.Cl.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[N:18]=[C:17]2[CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+]>C(O)C>[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[N:18]=[C:17]2[CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:2][C:3]([NH2:5])=[O:4])[CH2:28][CH2:27]2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(Cn2c(CC3CCNCC3)nc3cccnc32)cc1
Reactant: NC(=O)CI
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: NC(=O)CN1CCC(Cc2nc3cccnc3n2Cc2ccc(F)cc2)CC1
Reaction time: 3 h
Yield: 44.5 %

Procedure:
A mixture of 9.3 parts of 2-iodoacetamide, 20.0 parts of 3-[(4-fluorophenylmethyl]-2-(4-piperidinylmethyl)-3H-imidazo[4,5-b]pyridine dihydrochloride, 17.0 parts of sodium hydrogen carbonate and 200 parts of ethanol was stirred for 3 hours at at reflux temperature. The salts were filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, methanol and ammonium hydroxide (90:9:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and 2-propanone. The product was filtered off and dried in vacuo at 60° C., yielding 8.5 parts (44.5%) of 4-[[3-[(4-fluorophenyl)-methyl]-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperidineacetamide; mp. 153.4° C. (148).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([Cl:15])=[CH:4][N:3]=1.[CH3:16][P:17]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([O:27][CH3:28])[CH:21]=1)([CH3:19])=[O:18].Cl>CN(C=O)C.C(O)C>[Cl:15][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][C:2]([NH:24][C:23]2[CH:25]=[CH:26][C:20]([P:17]([CH3:16])([CH3:19])=[O:18])=[CH:21][C:22]=2[O:27][CH3:28])=[N:3][CH:4]=1
Reactant: COc1cc(P(C)(C)=O)ccc1N
Reactant: Clc1ncc(Cl)c(Nc2ccccc2)n1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1cc(P(C)(C)=O)ccc1Nc1ncc(Cl)c(Nc2ccccc2)n1
Yield: 16 %

Procedure:
To a solution of 2,5-dichloro-N-phenylpyrimidin-4-amine (84 mg, 0.35 mmol) and 4-(dimethylphosphoryl)-2-methoxyaniline (60 mg, 0.30 mmol) in 1 mL of DMF, was added 0.36 mL of 2.5M HCl in Ethanol. The reaction mixture was heated in a sealed tube at 140 degrees over night. The reaction mixture was filtered through a syringe filter and purified by Prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield the desired product as a white solid. (23 mg, 16% yield). MS/ES+: m/z=403
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]#[C:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([NH:18]C(=O)OC(C)(C)C)[CH2:13]2)=[CH:4][N:3]=1.[ClH:26]>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]#[C:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([NH2:18])[CH2:13]2)=[CH:4][N:3]=1.[ClH:26]
Reactant: COc1nc(Cl)ncc1C#C[C@@H]1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: COc1nc(Cl)ncc1C#C[C@@H]1CCC[C@H](N)C1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl ((1S,3R)-3-((2-chloro-4-methoxypyrimidin-5-yl)ethynyl)cyclohexyl)carbamate (Q2, 118 mg) in 1,4-dioxane (3 mL), a 4.0 mol/L solution of hydrochloric acid in 1,4-dioxane (3 mL) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, a 4.0 mol/L solution of hydrochloric acid in 1,4-dioxane (3 mL) was added at room temperature, and the mixture was stirred at the same temperature for 50 minutes. The solvent was evaporated under reduced pressure to obtain (1S,3R)-3-((2-chloro-4-methoxypyrimidin-5-yl)ethynyl)cyclohexaneamine (Q3) hydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][C:8](=[O:9])[C:4]=2[CH:3]=1.[CH3:12]OC(OC)OC.C([O-])(O)=O.[Na+].CCCCCC>CO.C(O)C.C(OCC)(=O)C>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH:7]=[C:8]([O:9][CH3:12])[C:4]=2[CH:3]=1
Reactant: O=C1COc2ccc(O)cc21
Reactant: COC(OC)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Solvent: CCO
Product: COc1coc2ccc(O)cc12
Yield: 73.3 %

Procedure:
900 mg (6.0 mmol) XVIII, 788 μl (7.2 mmol) orthoformic acid trimethyl ester and 57 mg (0.3 mmol) p-toluenesulfonic aid monohydrate were heated under reflux for 12 h in 70 ml methanol. The reaction was stopped by addition of saturated NaHCO3 solution and the solvent was removed. Subsequent flash chromatography (100 g SiO2, n-hexane:ethyl acetate=2:1, applied with ethanol) yielded 717 mg (4.4 mmol, 73%) XXI.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]([F:25])([F:24])[C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[C:16]([F:15])([F:24])[F:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2C(F)(F)F)CC1
Reaction time: 14 h
Yield: 307.8 %

Procedure:
To a stirred solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.20 g, 0.0001 mole) in dry 1,2-dichloroethane (7 mL) under an atmosphere of nitrogen for 10 minutes, was added 2-trifluoromethylaniline (0.161 g, 0.0001 mole), acetic acid (0.06 g, 0.0001 mole) and sodium triacetoxyborohydride (1.05 g, 0.0005 mole). The stirring was continued at ambient temperature for 14 hours. The reaction mixture was then quenched in cold aqueous 1N NaOH solution and the product extracted with ether. The ether layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to get the crude product as transparent viscous liquid. Purification by column chromatography using silica gel 60-120 mesh (2% ethyl acetate in hexane) afforded 0.106 g (31%) of 4-(2-trifluoromethyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (DMSO-d6): δ 7.4 (t, 2H), 7.0 (d, 1H), 6.7 (t, 1H), 3.9 (m, 2H), 2.9 (m, 2H), 1.9 (m, 2H), 1.4 (s, 9H). To a solution of 4-(2-trifluoromethyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.106 g, 0.000307 mole) in dioxane (0.5 mL) which was cooled to 0° C., was added, dioxane.HCl (2.5 mL) and the mixture was stirred at the same temperature for 10 minutes. The reaction mixture was gradually brought to ambient temperature and stirring was continued for 15 minutes. The reaction mixture was evaporated under reduced pressure and the resulting residue was washed with dry ether to afford 0.04 g (41%) of piperidin-4-yl-(2-trifluoromethyl-phenyl)-amine dihydrochloride. 1H NMR (DMSO-d6): δ 7.41 (t, 2H), 7.0 (d, 2H), 6.75 (t, 1H), 4.8 (d, 1H), 3.7 (bs, 1H), 3.3 (bs, 1H), 3.0 (m, 2H), 2.1 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([Cl:17])[CH:11]=2)=[O:8])[O:4][N:3]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[Cl:17][C:12]1[CH:11]=[C:10]([NH:9][C:7]([C:5]2[O:4][N:3]=[C:2]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:6]=2)=[O:8])[CH:15]=[CH:14][C:13]=1[F:16]
Reactant: O=C(Nc1ccc(F)c(Cl)c1)c1cc(Br)no1
Reactant: C1COCCN1
Product: O=C(Nc1ccc(F)c(Cl)c1)c1cc(N2CCOCC2)no1
Yield: 42 %

Procedure:
A solution of 3-bromo-N-(3-chloro-4-fluorophenyl)isoxazole-5-carboxamide (7.5 mg, 0.024 mmol) in morpholine (1.0 mL) was heated at 180° C. in the microwave for 15 minutes. Purification by preparative LCMS (pH 10 buffer) gave the desired product (3.2 mg, 42%). MF=C14H14ClFN3O3; LCMS calculated for C14H14ClFN3O3 (M+H)+: m/z=326.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:6][N:5]=[C:4]([N:17]=[CH:18]N(C)C)[N:3]=1.C([OH:25])(C)C.CS(O)(=O)=O>O>[Cl:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:6][N:5]=[C:4]([NH:17][CH:18]=[O:25])[N:3]=1
Reactant: CN(C)C=Nc1ncc(C#Cc2ccc(Cl)cc2)c(Cl)n1
Reactant: CC(C)O
Agent: CS(=O)(=O)O
Solvent: O
Product: O=CNc1ncc(C#Cc2ccc(Cl)cc2)c(Cl)n1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
4-Chloro-5-(4-chlorophenylethynyl)-2-dimethylaminomethyleneaminopyrimidine (65.1 g), isopropanol (585 mL), and water (36 mL) were combined and warmed to 60° C. Methane sulfonic acid (23.1 g) was added and heating at 60oC was continued for 1.5–2.0 hours or until HPLC analysis confirmed the absence of the starting material. The mixture was cooled to ambient temperature and held for 1.5 hours. The solids were removed by filtration and washed with isopropanol (100 mL). The filter cake was slurried in water (500 mL), basified with 1 N NaOH to pH 11, filtered, and the solids were rinsed with water. Vacuum drying at 50° C. provided predominantly 4-chloro-5-(4-chlorophenylethynyl)-2-formamidopyrimidine: 51.6 g.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[N:4][N:3]=1.[Cl:13][CH:14]([Cl:33])[C:15]([NH:17][C@H:18]([CH2:31][F:32])[C@H:19]([OH:30])[C:20]1[CH:25]=[CH:24][C:23]([Sn](C)(C)C)=[CH:22][CH:21]=1)=[O:16]>>[Cl:13][CH:14]([Cl:33])[C:15]([NH:17][C@H:18]([CH2:31][F:32])[C@H:19]([OH:30])[C:20]1[CH:21]=[CH:22][C:23]([C:2]2[S:6][C:5]([CH2:7][NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[N:4][N:3]=2)=[CH:24][CH:25]=1)=[O:16]
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Reactant: CS(=O)(=O)NCc1nnc(Br)s1
Product: CS(=O)(=O)NCc1nnc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)s1

Procedure:
Following the general procedure of Example 9—Step 2 and making non-critical variations but using N-((5-bromo-1,3,4-thiadiazol-2-yl)methyl)methanesulfonamide and 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(trimethyl-stannyl)phenyl)-propan-2-yl)acetamide the title compound is obtained (11.8 mg): 1H NMR (400 MHz, DMSO-d6) 3.0 (s, 3H), 4.2-4.4 (m, 1.5H), 4.45 (t, 1H), 4.55-4.6 (m, 0.5H), 4.65 (d, 2H), 4.7-4.75 (m, 0.5H), 4.95 (bt, 0.5H), 6.1 (d, 1H), 6.5 (s, 1H), 7.5 (d, 2H), 7.95 (d, 2H), 8.15 (t, 1H), 8.6 (d, 1H). m/z (CI) M+H 471.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]([CH3:19])[CH2:9][CH2:10][O:11][C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=1.C1(=O)O[CH2:23][CH2:22][O:21]1>CS(C)=O>[CH3:7][N:8]([CH3:19])[CH2:9][CH2:10][O:11][C:12]1[C:17]([O:18][CH2:23][CH2:22][OH:21])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: O=C1OCCO1
Reactant: CN(C)CCOc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN(C)CCOc1ncccc1OCCO
Temperature: 58 °C

Procedure:
DMSO (17 L) and potassium carbonate (8.2 kg) were charged to the 100 L-glasslined reactor. The mixture was heated to 58° C. while stirring. 2-(2-Dimethylaminoethoxy)pyridin-3-ol (4.11 kg) was charged to the reactor during 25 minutes (gas evolution). The mixture was heated to 117° C. before the prepared ethylene carbonate solution was added through the manhood in portions. After 1 L ethylene carbonate solution was added IP-HPLC was taken to ensure that the title compound had started to form. The total addition of ethylene carbonate solution was made during 1 h 35 minutes. Temperature after the addition was 124° C. A HPLC sample was taken from the reaction mixture 10 minutes after finished addition. It showed 95% conversion to product. The reaction-mixture was allowed to cool to 70° C. before water (45 L) and sodium chloride (4.06 kg) was charged to the reactor. The mixture was then stirred for 20 minutes at 70° C. before cooled to RT. Ethyl acetate (137 L) was charged into a 328 L glass-lined reactor. The water mixture was transferred from the 100 L reactor to the 328 L reactor. The mixture was stirred for 25 minutes before the mechanical stirrer was turned off. After allowing the phases to separate for 40 minutes, the water-phase (65 L) was discharged. The mixture was heated to reflux and 102 L of ethyl acetate was distilled off. Toluene (72 L) was added and the mixture was heated to reflux again and 61 L of toluene/ethyl acetate was distilled off. The reaction mixture was then cooled to RT. The title compound was never isolated; it was directly used in Example 2C.
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13](CC4C=CC(OC)=CC=4)[N:14]=[C:15]([NH:16][CH:17]4[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][OH:25])[CH2:19][CH2:18]4)[C:8]=23)=[C:4]([F:37])[CH:3]=1.[F:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]2[C:50](=[O:51])[C:49]([C:52](O)=[O:53])=[CH:48][CH:47]=[N:46]2)=[CH:41][CH:40]=1>>[F:37][C:4]1[CH:3]=[C:2]([NH:1][C:52]([C:49]2[C:50](=[O:51])[N:45]([C:42]3[CH:43]=[CH:44][C:39]([F:38])=[CH:40][CH:41]=3)[N:46]=[CH:47][CH:48]=2)=[O:53])[CH:36]=[CH:35][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[NH:13][N:14]=[C:15]([NH:16][CH:17]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][OH:25])[CH2:21][CH2:22]3)[C:8]=12
Reactant: COc1ccc(Cn2nc(NC3CCN(CCO)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Product: O=C(Nc1ccc(Oc2ccnc3[nH]nc(NC4CCN(CCO)CC4)c23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Yield: 55 %

Procedure:
Prepared by a 2-step process from 2-(4-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)piperidin-1-yl)ethanol (prepared as described in Example 101, Step A except using 2-(4-aminopiperidin-1-yl)ethanol) and 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid according to the procedure of Example 101, Step B. The crude material was rinsed with Et2O to afford 11 mg (55%) of the desired product. LRMS (ESI pos) m/e 603.1 (M+1). 1H-NMR (400 MHz, CD3OD/CDCl3) δ 8.42 (d, 1H), 8.31 (d, 1H), 8.13 (d, 1H), 8.0 (dd, 1H), 7.63 (m, 2H), 7.45 (d, 1H), 7.33 (t, 1H), 7.28 (t, 2H), 6.10 (d, 1H), 3.72 (m, 3H), 3.03 (m, 2H), 2.65 (m, 2H), 2.40 (m, 2H), 2.25 (m, 2H), 1.67 (m, 2H); 19F NMR (376 MHz, CD3OD/CDCl3) δ −112.1, −126.9.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8](I)=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:13][C:14]1[CH:15]=[CH:16][C:17]2=[C:18]([CH:34]=1)[O:19][CH2:20][C:21]1[CH:31]=[C:30]([CH:32]=[O:33])[CH:29]=[CH:28][C:22]=1/[C:23]/2=[C:24](/[CH3:27])\[C:25]#[N:26]>>[F:13][C:14]1[CH:15]=[CH:16][C:17]2=[C:18]([CH:34]=1)[O:19][CH2:20][C:21]1[CH:31]=[C:30]([CH:32]([C:8]3[N:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]4=[N:10][C:9]=3[CH3:11])[OH:33])[CH:29]=[CH:28][C:22]=1/[C:23]/2=[C:24](/[CH3:27])\[C:25]#[N:26]
Reactant: Cc1nc2c(Cl)cccn2c1I
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Product: C/C(C#N)=C1/c2ccc(C(O)c3c(C)nc4c(Cl)cccn34)cc2COc2cc(F)ccc21
Yield: 91.7 %

Procedure:
[step 3] Using 8-chloro-2-methyl-3-iodoimidazo[1,2-a]pyridine (598 mg, 2.05 mmol) obtained in step 2 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (300 mg, 1.02 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8A, step 3, (E)-2-{3-fluoro-8-[(8-chloro-2-methylimidazo[1,2-a]pyridin-3-yl)(hydroxy)methyl]dibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (430 mg, 91%) was obtained.
Reaction SMILES: C[O:2][C:3](=[O:26])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]1=[O:25])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+].Cl>O1CCCC1.O>[CH3:7][CH:6]([CH3:8])[CH2:5][C@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]1=[O:25])[C:3]([OH:26])=[O:2]
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2cccc3ccccc23)=CC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc3ccccc23)=CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.9 %

Procedure:
A mixture of (S)-4-methyl-2-[4-(naphthalen-1-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid methyl ester (0.38 g, 1.08 mmol) in tetrahydrofuran (8.1 mL) and water (2.7 mL) was treated with lithium hydroxide monohydrate (54 mg, 1.3 mmol). The reaction was stirred at 25° C. for 2 h. At this time, the reaction was diluted with water (50 mL), acidified with a 2N aqueous hydrochloric acid solution and then extracted with 10% methanol/dichloromethane (3×50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford (S)-4-methyl-2-[4-(naphthalen-1-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid (0.37 g, 99%) as a pale yellow solid: HR-ES-MS m/z calculated for C20H21NO4 [M+H]+ 340.1544, observed 340.1545; The material was used without further purification. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.3 Hz, 3H), 0.95 (d, J=6.3 Hz, 3H), 1.43-1.88 (m, 3H), 4.33 (d, J=18.1 Hz, 1H), 4.42 (d, J=18.1 Hz, 1H), 4.64 (dd, J=11.3, 4.4 Hz, 1H), 4.74 (s, 1H), 7.51 (d, J=7.5 Hz, 1H), 7.54-7.68 (m, 3H), 7.91 (d, J=8.2 Hz, 1H), 7.96-8.09 (m, 2H), 12.89 (br. s., 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:18](O)([CH3:20])[CH3:19])[CH:14]=[CH:15][C:16]=1[CH3:17])[CH3:9].P(Cl)(Cl)(Cl)=O.O.[OH-].[Na+]>N1C=CC=CC=1>[CH3:1][C:2]([CH3:23])([CH3:22])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:18]([CH3:20])=[CH2:19])[CH:14]=[CH:15][C:16]=1[CH3:17])[CH3:9]
Reactant: Cc1ccc(C(C)(C)O)cc1CN(C)C/C=C/C#CC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: C=C(C)c1ccc(C)c(CN(C)C/C=C/C#CC(C)(C)C)c1
Temperature: 135 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
Compound 33 (520 mg; 1.66 mmol) was dissolved in pyridine (6 ml), and phosphorus oxychloride (1.27 g; 8.3 mmol) was added thereto. The mixture was stirred for 1 hour at 130-140° C., and then cooled. The reaction mixture was poured into water, and alkalinized with sodium hydroxide pellet. The mixture was extracted with ether (120 ml), and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1), to thereby yield 420 mg of the target compound (yield: 85.7%).
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:15][CH2:16][C:17]1[CH:18]=[C:19]([Si:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:23][CH3:24])[O:20][CH:21]=1.C(N(CC)CC)C>O1CCCC1>[C:1]([NH:15][CH2:16][C:17]1[CH:18]=[C:19]([Si:22]([CH2:25][CH3:26])([CH2:27][CH3:28])[CH2:23][CH3:24])[O:20][CH:21]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC[Si](CC)(CC)c1cc(CN)co1
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)NCc1coc([Si](CC)(CC)CC)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Dodecanoyl chloride (109 mg, 0.49 mmol) was added to a solution of 4-aminomethyl-2-triethylsilylfuran (Compound 2, 70 mg, 0.33 mmol) and triethylamine (69 microliter, 0.49 mmol) in tetrahydrofuran (3 ml) at room temperature. After stirring at room temperature overnight (ca. 15 hours), most of the solvent was evaporated and the residue was purified by chromatography on preparative silica thin layer plates (developed with 50% ethyl ether/hexane) to give the title amide as a colorless oil.
Reaction SMILES: [CH:1]1([C:5]([NH:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[S:22]1[CH:26]=[CH:25][N:24]=[C:23]1[NH:27][C:28](=O)[O:29]C1C=CC=CC=1.CS(C)=O.O>C(OCC)(=O)C>[CH:1]1([C:5]([NH:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:16]=[CH:17][C:18]([NH:19][C:28]([NH:27][C:23]4[S:22][CH:26]=[CH:25][N:24]=4)=[O:29])=[CH:20][CH:21]=3)[CH:11]=[CH:10][N:9]=2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(Nc1nccs1)Oc1ccccc1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)C3CCC3)c2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(Nc1ccc(Oc2ccnc(NC(=O)C3CCC3)c2)cc1)Nc1nccs1

Procedure:
4-(2-Cyclobutanecarbonylaminopyridin-4-yl)oxyaniline (130 mg), phenyl N-(2-thiazolyl)carbamate (110 mg) and dimethylsulfoxide (3 ml) were stirred at 80° C. for 30 minutes. Water and ethyl acetate were added to the reaction solution for extraction, and the ethyl acetate layer was washed 5 times with aqueous ammonium chloride solution and then dried over magnesium sulfate. The drying agent was filtered off, the solvent was distilled off under reduced pressure, ethyl acetate was added to the residue and the precipitated solid was filtered out to obtain 130 mg of the target substance as a light brown solid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2=[CH:17][S:18][CH:19]=[C:6]12)=[O:4].[N:20]1([CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]2)[CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[N:20]1([CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][N:27]2[CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8](=[O:16])[C:7]3=[CH:17][S:18][CH:19]=[C:6]23)=[O:4])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1Nc2ccccc2N(C(=O)CCl)c2cscc21
Reactant: C1CCC(CN2CCCC2)NC1
Solvent: CC#N
Product: O=C1Nc2ccccc2N(C(=O)CN2CCCCC2CN2CCCC2)c2cscc21

Procedure:
The title compound is prepared analogously to Example 2 from 4-(chloroacetyl)-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2-[(1-pyrrolidinyl)methyl]piperidine to give colorless crystals, Mp. 205°-207° C. (acetonitrile/activated charcoal).