Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[C:15]([F:22])[CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=2)=[C:15]([F:22])[CH:14]=1
Reactant: COC(=O)c1cnccc1Cl
Reactant: OB(O)c1ccc(Cl)cc1F
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cnccc1-c1ccc(Cl)cc1F
Yield: 46.1 %

Procedure:
To a stirred solution of methyl 4-chloronicotinate (7 g, 40.8 mmol), (4-chloro-2-fluorophenyl)boronic acid (7.11 g, 40.8 mmol) and cesium carbonate (26.6 g, 82 mmol) in a mixture of dioxane (60 mL) and water (8 mL) purged with nitrogen gas for 5 min, was added Pd(PPh3)4 (2.83 g, 2.448 mmol) and the resultant mixture was heated at 85° C. for 15 h. Water (30 mL) was added and the mixture was extracted with EtOAc (1×50 mL). The organic layer was washed with water (1×30 mL) and brine (1×30 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via silica gel column (30% EtOAc in hexane) to give methyl 4-(4-chloro-2-fluorophenyl)nicotinate (5 g, 18.82 mmol, 40% yield). LCMS (ESI) m/e 266.7 [(M+H)+, calcd for C13H10ClFNO2 266.0]; LCMS retention time (Method C): tR=1.73 min.
Reaction SMILES: [CH2:1]([C:3]1([CH2:7][OH:8])[CH2:6][O:5][CH2:4]1)[CH3:2].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1([CH2:7][O:8][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:6][O:5][CH2:4]1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCC1(CO)COC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCC1(COS(C)(=O)=O)COC1
Yield: 100 %

Procedure:
After adding 3-ethyl-3-hydroxymethyloxetane (465 g (4.0 mol)), triethylamine (486 g (4.8 mol)) and toluene (1,840 ml) to a glass flask having an inner volume of 5,000 ml equipped with a stirrer, a thermometer and a dropping funnel, while keeping the liquid temperature at 5-10° C., methanesulfonyl chloride (504 g (4.4 mol)) was gradually added to react at the same temperature for 3 hours and at room temperature for 3 hours with stirring. After the completion of the reaction, an aqueous saturated sodium bicarbonate solution (930 ml) was added to the reaction solution and a liquid separation was performed. Subsequently an aqueous layer was extracted with toluene (930 ml), an extract was combined with a previously extracted organic layer, and the combined liquid was washed with water (465 ml). A resultant organic layer was concentrated under reduced pressure to give, as a brown liquid, 3-ethyl-3-methanesulfonyloxymethyloxetane (777 g) having a purity of 95% (a value measured by 1H-NMR) (an isolated yield based on 3-ethyl-3-hydroxymethyloxetane: 95%).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17]([O:19]CC)=[O:18])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[CH:10][C:11]=1[F:12].[OH-].[Li+]>C1COCC1.C(O)C>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17]([OH:19])=[O:18])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[CH:10][C:11]=1[F:12]
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)c(F)ccn12
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1nc2c(OCc3c(F)cccc3F)c(F)ccn2c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
365 mg (0.76 mmol; purity about 76%) of ethyl 8-[(2,6-difluorobenzyl)oxy]-7-fluoro-2-methylimidazo[1,2-a]pyridine-3-carboxylate Example 111A were dissolved in 16.6 ml of THF/ethanol (5:1), 1.14 ml (1.14 mmol) of 1 N aqueous lithium hydroxide solution were added and the mixture was stirred at RT overnight. Another 2.67 ml (2.67 mmol) of 1 N aqueous lithium hydroxide solution were added, and the mixture was stirred at RT overnight. The mixture was concentrated and the aqueous phase was acidified to pH 4 using 6 N hydrochloric acid. A precipitate formed, and the suspension was cooled with ice water. The solid was filtered off and dried under high vacuum. This gave 236 mg of the target compound (87% of theory, purity 94%).
Reaction SMILES: C([O:8][C:9](=[O:34])[CH2:10][N:11]1[CH2:33][CH2:32][CH2:31][C@H:12]1[C:13]([N:15]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:16](=[O:23])[C@H:17]([C@H:19]([CH2:21][CH3:22])[CH3:20])[NH2:18])=[O:14])C1C=CC=CC=1.[H][H]>[Pd].CO>[C:9]([CH2:10][N:11]1[CH2:33][CH2:32][CH2:31][C@H:12]1[C:13]([N:15]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:16](=[O:23])[C@H:17]([C@H:19]([CH2:21][CH3:22])[CH3:20])[NH2:18])=[O:14])([OH:34])=[O:8]
Reactant: [H][H]
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Temperature: 22 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
Using the hydrogenation conditions described in example 4, a solution of L-isoleucine, N-[1-(2-benzyloxy-2-oxoethyl)-L-prolyl] benzylamide (14.80 g, 31.76 mmol), 10% palladium on carbon (0.80 g), and methanol (350 mL), was purged with hydrogen, and stirred under an atmosphere of hydrogen at 22° C. After 8 hrs, the solution was purged with argon, filtered through a plug of celite, and concentrated in vacuo to provide 11.47 g, (96%) of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]([CH2:13][CH3:14])[CH2:9][CH:10]([OH:12])[CH3:11])=[CH:6][CH:7]=1.[C:15]([NH:20][NH2:21])([O:17][CH2:18][CH3:19])=[O:16].C(O)CCCC>>[C:15]([NH:20][NH:21][C:2]1[N:3]=[N:4][C:5]([N:8]([CH2:13][CH3:14])[CH2:9][CH:10]([OH:12])[CH3:11])=[CH:6][CH:7]=1)([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)NN
Reactant: CCN(CC(C)O)c1ccc(Cl)nn1
Solvent: CCCCCO
Product: CCOC(=O)NNc1ccc(N(CC)CC(C)O)nn1
Reaction time: 4 h

Procedure:
A mixture of 11 g 3-chloro-6-[N-(2-hydroxypropyl)ethylamino]pyridazine which can be be prepared as described in Example 4 of U.S. Pat. No. 3,769,278 and 11 g monocarbethoxyhydrazine in 55 ml n. pentylalcohol is warmed up to 140° C and kept at this temperature for 4 hours. After cooling the solution is extracted several times with water and then extracts collected together are extracted with ethyl ether. The aqueous phase is treated at room temperature with sodium bicarbonate until complete precipitation. The precipitate is collected, washed with water and dried under vacuum at room temperature on phosphorus pentaoxide to give with good yield 3-(2-carbethoxyhydrazino)-6-[N-(2-hydroxypropyl)ethylamino]-pyridazine melting at 160° -162° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][N:13]=1>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Br)nc1
Reactant: OB(O)c1ccc(O)cc1
Product: N#Cc1ccc(-c2ccc(O)cc2)nc1
Yield: 23 %

Procedure:
The title compound was prepared according to the method described for Preparation 17 using 4-hydroxybenzene boronic acid and 2-bromo-5-cyanopyridine to afford the title compound as a white solid (250 mg, 23%)
Reaction SMILES: [OH:1][C@@H:2]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])=[CH:7][CH:6]=1)[CH2:3][OH:4].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.O>N1C=CC=CC=1>[CH3:31][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O:4][CH2:3][C@H:2]([C:5]2[CH:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:20])[CH3:12])=[CH:7][CH:6]=2)[OH:1])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc([C@H](O)CO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)c2ccc([C@H](C)NC(=O)OC(C)(C)C)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
4.32 g of the compound [5-2] was dissolved in 50 mL of pyridine, and 3.66 g of p-toluenesulfonyl chloride was added thereto under an ice-cold condition. The reaction mixture was stirred overnight at 0° C., water was added thereto, and then the mixture was extracted with ethyl acetate, and the resulting organic layer was dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and then the obtained residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=50/50-0/100), to obtain 6.52 g of (2S)-2-(4-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}phenyl)-2-hydroxyethyl 4-methylbenzenesulfonate [5-3] (hereinafter, referred to as the compound [5-3]) as a colorless amorphous.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([C:13](=O)[CH3:14])[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>O1CCCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11](/[C:13](=[N:22]/[S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])/[CH3:14])[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cnn(-c2cccc(Br)c2)c1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Product: C/C(=N\[S@](=O)C(C)(C)C)c1cnn(-c2cccc(Br)c2)c1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
A solution of 1-[1-(3-bromo-phenyl)-1H-pyrazol-4-yl]-ethanone (1.0 g, 4.53 mmol), (R)-2-methylpropane-2-sulfinic acid amide (0.66 g, 5.43 mmol) and titanium (IV) ethoxide (2.1 ml, 9.96 mmol) in tetrahydrofuran (20 ml) was refluxed for 12 hours. The reaction mixture was cooled to 25° C., quenched with brine (20 ml), and extracted with ethyl acetate (5×20 ml). The combined organic layers were washed with brine (50 ml), dried over sodium sulphate, and evaporated at reduced pressure. The crude material thus obtained was purified by column chromatography on silica gel using a gradient of hexane/ethyl acetate=85:15 to 80:20 as the eluent to give the (R)-2-methyl-propane-2-sulfinic acid [1-[1-(3-bromo-phenyl)-1H-pyrazol-4-yl]-eth-(E)-ylidene]-amide (1.0 g, 60% yield) as a yellow solid. MS (ISP): m/z=368.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].C([Li])CCC.[CH2:18]([Sn:22](Cl)([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21]>O1CCCC1>[CH2:11]([O:10][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[S:6][C:7]([Sn:22]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:8][CH:9]=1)[CH3:12]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CCOC(OCC)c1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C(OCC)OCC)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
18.6 g (100 mmol) of 2-(diethoxymethyl) thiophene in 100 ml of tetrahydrofuran ("THF") was placed in a 2-neck flask equipped with dropping funnel. The solution was cooled to -78° C. under nitrogen atmosphere and added 62.5 mL of 1.6 M n-butyl lithium (100 mmol) dropwise through dropping funnel in 1 hr. The reaction mixture was stirred at -78° C. for 1 hr and gradually warmed up to room temperature. After stirred for 30 minutes, the mixture was again cooled to -78° C. and added dropwise a THF (50 mL) solution of 32.5 g (100 mmol) of tributyl tin chloride with continual stirring. Gradually warmed up to room temperature, the mixture was stirred for another 10-12 hrs at room temperature and then concentrated. Reduced pressure distillation yielded 36.8 g (80%) of 2-(diethoxymethyl)-5-(tributylstannyl) thiophene (bp 195° C./1 torr).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.[CH2:17]=O.S(=O)(=O)(O)O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:6][CH2:7][N:8]([C:9](=[O:14])[C:10]([F:12])([F:13])[F:11])[CH2:17]2)=[CH:15][CH:16]=1
Reactant: C=O
Reactant: O=C(NCCc1ccc(Br)cc1)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(N1CCc2ccc(Br)cc2C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of N-(4-bromophenethyl)-2,2,2-trifluoroacetamide (8.88 g, 30 mmol) and paraformaldehyde (13.5 g, 0.45 mol) in 45 mL of glacial acetic acid at room temperature was slowly added 30 mL of sulfuric acid (96.6%). After stirring at room temperature overnight, the reaction mixture was quenched with ice water and extracted with EtOAc, washed with brine and Sat. NaHCO3 and dried over Na2SO4. After concentration, flash chomatography (SiO2, hexane/DCM=1:1) gave 1-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:17][C:11]3[C:12](=[O:16])[NH:13][N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH2:25][C:26]1[N:31]=[C:30]([O:32][CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH:29]=[CH:28][CH:27]=1)(=O)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:17][C:11]3[C:12](=[O:16])[N:13]([CH2:25][C:26]4[N:31]=[C:30]([O:32][CH:33]5[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:38]5)[CH:29]=[CH:28][CH:27]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]ncc2cc(-c3ccc(Cl)cc3)sc12
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(COS(C)(=O)=O)n2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(Cn3ncc4cc(-c5ccc(Cl)cc5)sc4c3=O)n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-(4-chlorophenyl)thieno[2,3-d]pyridazin-7(6H)-one (0.32 g, 1.22 mmol) in DMF (10 mL) was added 60% sodium hydride in oil (0.06 g, 1.34 mmol, 55%). Stirred for 10 minutes under N2 atmosphere before addition of tert-butyl 4-[(6-{[(methylsulfonyl)oxy]methyl}pyridin-2-yl)oxy]piperidine-1-carboxylate (crude product from step d) dissolved in DMF (10 mL). The resulting mixture was stirred for 18 hours at room temperature followed by prep-HPLC purification to give the product. Yield: 0.22 g (32% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.60-7.64 (m, 2H), 7.40-7.51 (m, 4H), 6.75 (d, 1H, J=7.28 Hz), 6.54 (d, 1H, J=8.24 Hz), 5.47 (s, 2H), 4.90-4.99 (m, 1H), 3.58-3.70 (m, 2H), 2.94-3.04 (m, 2H), 1.73-1.82 (m, 2H), 1.47-1.60 (m, 2H), 1.39 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 162.9, 157.3, 155.1, 153.7, 152.5, 140.3, 139.5, 136.4, 136.1, 133.1, 131.2, 129.8, 128.3, 118.9, 114.2, 110.3, 79.7, 70.6, 55.7, 41.3, 30.8, 28.7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][CH2:12][C:13]([NH:15][C:16]([C:18]1[C:23](Cl)=[N:22][CH:21]=[CH:20][N:19]=1)=[O:17])=[NH:14].CC([O-])(C)C.[K+].O.Cl>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][CH2:12][C:13]1[NH:15][C:16](=[O:17])[C:18]2[C:23](=[N:22][CH:21]=[CH:20][N:19]=2)[N:14]=1
Reactant: N=C(COCCc1cc(F)ccc1F)NC(=O)c1nccnc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=c1[nH]c(COCCc2cc(F)ccc2F)nc2nccnc12
Temperature: 45 °C
Yield: 23.5 %

Procedure:
Crude 3-chloro-pyrazine-2-carboxylic acid{2-[2-(2,5-difluoro-phenyl)-ethoxy]-1-imino-ethyl}-amide (190 mg) was dissolved in DMSO (1 ml). KOtBu (60 mg, 0.536 mmol) was added and the mixture was heated to 45° C. for 2.5 h. Then water was added, the pH was adjusted to 6 by addition of 0.1 N HCl and the resulting mixture was extracted three times with CH2Cl2. The combined extracts were washed with water (three times) and brine, dried (Na2SO4) and evaporated. The resulting orange brown solid was triturated with Et2O. The remaining solid was filtered off, washed with a small amount of Et2O and dried to give the title compound as a light brown solid (40 mg, 23%). MS: m/e=319.1 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23]([O:25]C)=O)[CH:5]=[CH:6][CH:7]=1.Cl.[OH-].[NH4+:29]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(F)c1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(F)c1
Yield: 45 %

Procedure:
A solution of the 9-[(3-fluorophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (130.8 mg, 0.37 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was sonicated for 5 h at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 57.4 mg (45%) of the 9-[(3-fluorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (dd, 1H, J=1 and 8 Hz), 7.5 (m, 2H), 7.3 (m, 2H), 7.15-7.0 (m, 2H), 6.95 (d, 1H, J=8 Hz), 6.85 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), and 5.7 (s, 2H). IR (CHCl3, cm−1) 3431, 3200 (br), 1628, 1614, 1600, 1580, 1546, 1488, 1448, 1329, 1261, and 776. MS (ES) m/e 333, 335.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([CH2:10][CH2:11][OH:12])[CH3:9])=[CH:6][C:5]([C:13]#[N:14])=[CH:4][C:3]=1[NH:15]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:15][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([CH:8]([CH2:10][CH2:11][OH:12])[CH3:9])[C:2]=1[Cl:1])[C:13]#[N:14]
Reactant: CC(CCO)c1cc(C#N)cc(NC(=O)OC(C)(C)C)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(CCO)c1cc(C#N)cc(N)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 127.4 %

Procedure:
Tert-butyl (2-chloro-5-cyano-3-(4-hydroxybutan-2-yl)phenyl)carbamate (184 mg, 0.566 mmol) was taken up in DCM (6 mL) and TFA (1.746 mL, 22.66 mmol) was added. The reaction was stirred at room temperature for 1 h. LCMS indicates a mixture of the alcohol and the TFA ester. The solvent was removed in vacuo and the material dissolved in 2N NH3 in MeOH. The solution was stirred at room temperature for 10 min and the solvent removed in vacuo. 3-amino-4-chloro-5-(4-hydroxybutan-2-yl)benzonitrile (162 mg) was obtained. The crude material was taken forward without purification.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]5[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]5)[CH:18]=4)[CH:16]=[C:11]3[CH:10]=[CH:9]2)=CC=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:30][N:27]1[CH2:26][CH2:25][N:24]([CH2:23][C:19]2[CH:18]=[C:17]([C:15]3[CH:16]=[C:11]4[CH:10]=[CH:9][NH:8][C:12]4=[N:13][CH:14]=3)[CH:22]=[CH:21][CH:20]=2)[CH2:29][CH2:28]1
Reactant: COc1ccc(Cn2ccc3cc(-c4cccc(CN5CCN(C)CC5)c4)cnc32)cc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(Cc2cccc(-c3cnc4[nH]ccc4c3)c2)CC1
Temperature: 50 °C

Procedure:
To a stirred solution of 1-(4-methoxybenzyl)-5-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridine (151) (30 mg) in CHCl3 (8 mL) was added trifluoroacetic acid (5 mL) and heated at 50° C. for 12. After completion of the reaction the solvents were removed, diluted with cold water, pH was adjusted to 8 and the aqueous phase extracted with CHCl3 twice. The organic layer was washed with brine solution and dried over sodium sulphate and the solvent completely distilled off to get the crude product. The crude was passed through 100-200 mesh silica gel, eluting the pure compound in 2% MeOH/CHCl3 gave pale yellow solid compound 5-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridine 152.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH3:21][C:22]1[C:26]([C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[CH:25][NH:24][C:23]=1[CH:36]=O>C(O)C.N1CCCCC1>[CH3:21][C:22]1[C:26]([C:27]([N:29]2[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)=[O:28])=[CH:25][NH:24][C:23]=1[CH:36]=[C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=2)[NH:13][C:12]1=[O:18]
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=C1C(=O)Nc2cccc(-c3cccc(C(F)(F)F)c3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.9 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (46.9 mg, 38%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22]([NH:25][C:26]3[S:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2.B1([C:40]2[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH:41]=2)OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[S:30]1[C:26]([NH:25][S:22]([C:19]2[CH:20]=[CH:21][C:13]3[N:12]([C:3]4[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=4[C:40]4[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH:41]=4)[CH2:17][CH2:16][O:15][C:14]=3[CH:18]=2)(=[O:24])=[O:23])=[N:27][CH:28]=[N:29]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=S(=O)(Nc1ncns1)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Br
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2N2CCOc3cc(S(=O)(=O)Nc4ncns4)ccc32)CC1
Temperature: 100 °C
Yield: 29.2 %

Procedure:
A microwave vial was charged with INTERMEDIATE D (0.100 g, 0.192 mmol), (N-tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (Maybridge Chemicals, Cornwall, UK, 0.059 mL, 0.192 mmol), tetrakis(triphenylphosphine)palladium(0) (0.022 g, 0.019 mmol), and K2CO3 (0.133 g, 0.959 mmol). The solids were diluted with dioxane (1.279 mL) and water (0.639 mL), and the reaction was heated under microwave irradiation at 100° C. for 10 minutes (starting material remained, but moved forward). The reaction mixture was diluted with water, and washed with DCM. Equal partitioning between both layers was observed (and an emulsion formed), so the organic and aqueous were combined and concentrated until just the water remained. The aqueous was washed with DCM (×3) and the organics were then combined and dried using a phase separator. After concentration, the material was purified by reverse-phase preparative HPLC (Column: Phenomenex 150×30 mm, 5 micron, C18 column; 0.1% TFA in CH3CN/H2O, gradient 25% to 90% over 20 min) to provide tert-butyl 4-(2-(7-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3 H)-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2 H)-carboxylate (0.035 g, 0.056 mmol) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.37 (s, 9 H) 2.16-2.37 (m, 2 H) 3.51-3.72 (m, 4 H) 3.81-3.90 (m, 2 H) 4.22-4.34 (m, 2 H) 5.84 (br. s., 1 H) 6.38-6.46 (m, 1 H) 7.10-7.17 (m, 2 H) 7.56 (d, J=8.31 Hz, 1 H) 7.65 (d, J=2.05 Hz, 1 H) 7.72 (dd, J=8.41, 2.15 Hz, 1 H) 8.42 (s, 1 H). m/z (ESI) 524.0 (Boc group falls off in LCMS).