Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[C:18]([CH3:19])=[C:17](/[CH:20]=[C:21]2\[C:22](=[O:31])[NH:23][C:24]3[C:29]\2=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[NH:16][C:15]=1[CH3:32])=[O:13])(C)(C)C.Cl>CO.O1CCOCC1>[NH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[C:18]([CH3:19])=[C:17](/[CH:20]=[C:21]2\[C:22](=[O:31])[NH:23][C:24]3[C:29]\2=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[NH:16][C:15]=1[CH3:32])=[O:13]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCN
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
[3-({5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carbonyl}-amino)-propyl]-carbamic acid tert-butyl ester was suspended in methanol. 2 ml of HCl (4N) in dioxane was added and the reaction stirred at room temperature overnight. The solvent was removed to yield the desired compound (0.098 g, 91%). 1H NMR (400 MHz, DMSO-d6) δ 13.8 (s, 1H); 11.00 (s, 1H); 7.90-7.70 (m, 5H); 6.9 (m, 2H); 3.30 (q, 2H); 2.80 (q, 2H); 2.50 (dd, 6H) 1.80 (m, 2H). LCMS: inconclusive due to fluorescence.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][CH2:28][O:29]C4CCCCO4)[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.Cl>C(Cl)Cl.O1CCOCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][CH2:28][OH:29])[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1
Reactant: Cn1ncc2cc(Cc3cnc4ccc(-c5cnn(CCOC6CCCCO6)c5)nn34)c(F)cc21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1ncc2cc(Cc3cnc4ccc(-c5cnn(CCO)c5)nn34)c(F)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(6-Fluoro-1-methyl-1H-indazol-5-yl methyl)-6-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-imidazo[1,2-b]pyridazine (Stage 281.1, 269 mg, 566 μmol) was dissolved in DCM (5 mL). HCl in dioxane (4 N, 283 μl) was added and the RM was stirred 1 h at rt. The solvent was totally evaporated and the residue was taken up with EtOAc and washed with saturated NaHCO3 and brine. The organic layer was dried over Na2SO4 and solvent evaporated under vacuo. The residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA). The acetonitrile was removed and the aqueous solution was basified with 5% NaHCO3. It was extracted 3 times with EtOAc and then the organics were joined and washed with brine. It was dried over Na2SO4 and the solvent was removed. The residue was triturated with pentane and the precipitate was filtered off to give the title compound a white solid (tR 0.93 min (conditions 2), MH+=392, 1H-NMR in DMSO-d6: 8.42 (s, 1H); 8.1 (s, 1H); 8.02 (d, 1H); 7.97 (s, 1H); 7.75 (d, 1H); 7.52 (t, 3H); 4.95 (m, 1H); 4.40 (s, 2H); 4.21 (t, 2H); 3.96 (s, 3H); 3.77 (m, 2H)).
Reaction SMILES: CN=[C:3]([OH:21])[C:4]1[C:5](=[C:9]([S:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([OH:8])=[O:7].Cl>[OH-].[Na+]>[CH2:17]([S:16][C:9]1[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=[C:4]2[C:3]([O:7][C:6](=[O:8])[C:5]=12)=[O:21])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCSc1cc([N+](=O)[O-])cc(C(O)=NC)c1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCSc1cc([N+](=O)[O-])cc2c1C(=O)OC2=O

Procedure:
883 mg (3 mmols) of 3-n-butylthio-5-nitrophthalic acid N-methylimide are kept under reflux overnight in 9 ml of 1 N sodium hydroxide solution and the mixture is acidified with 10 ml of 2 N hydrochloric acid and, after 5 minutes under reflux, cooled. The mixture is extracted with tetrahydrofuran/toluene and the extracts are washed with saturated NaCl solution, dried over sodium sulfate and evaporated. The resulting acid is converted to the anhydride with 1 ml of acetic anhydride and 10 ml of toluene, by heating and evaporation. After recrystallisation from cyclohexane, 790 mg (94% of theory) of the title anhydride are obtained as a yellow product; melting point: 95°-97° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[C:7]([NH:9][C:10]1[S:11][CH:12]=[CH:13][C:14]=1[C:15]([NH2:17])=[O:16])=O)[CH2:2][CH3:3].[OH-].[Na+].Cl>N1C=CC=CC=1>[CH2:1]([O:4][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[C:7]1[NH:17][C:15](=[O:16])[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[N:9]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1C(=O)Nc1sccc1C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCCOc1ccccc1-c1nc2sccc2c(=O)[nH]1

Procedure:
A stirred mixture of 2-(propoxybenzamido)-thiophene-3-carboxamide (0.90 g) and pyridine (1 ml) in 2 Normal sodium hydroxide (25 ml) was heated under reflux for 2 hours. The cooled reaction mixture was neutralised with concentrated hydrochloric acid to afford a precipitate and the resulting mixture was extracted with chloroform (3×25 ml). The combined extracts were washed with water (20 ml) and brine (20 ml), dried (magnesium sulphate) and evaporated under reduced pressure to afford a crude product which was recrystallised from ethanol-water to afford the title compound, 0.41 g, m.p. 115°-117° C.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH:6]=[C:7]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=3[C:21](=[O:23])[CH3:22])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:24][Mg]Cl.Cl>O1CCCC1>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH:6]=[C:7]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=3[C:21]([OH:23])([CH3:24])[CH3:22])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1c(F)cccc1Oc1cnc2c(F)c(F)ccc2c1
Reactant: C[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(O)c1c(F)cccc1Oc1cnc2c(F)c(F)ccc2c1
Temperature: 0 °C

Procedure:
After 0.64 g of 1-[2-(7,8-difluoroquinolin-3-yloxy)-6-fluoro-phenyl]-ethanone was dissolved in 10 ml of tetrahydrofuran, the resultant was cooled to 0° C. and 1.5 ml of methylmagnesium chloride (3.0 M tetrahydrofuran solution) was added dropwise. Dilute hydrochloric acid was added to the reaction solution, and the liquid was separated with ethyl acetate. The organic layer was concentrated and purified by silica gel column chromatography to obtain 0.49 g of 2-[2-(7,8-difluoroquinolin-3-yloxy)-6-fluoro-phenyl]-propan-2-ol (Compound Number 124).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl.[Cl:9][CH2:10][C:11]1[C:16]([CH3:17])=[C:15]([S:18][CH2:19][CH2:20][CH2:21][Cl:22])[CH:14]=[CH:13][N:12]=1>C(O)(C)C>[ClH:9].[Cl:22][CH2:21][CH2:20][CH2:19][S:18][C:15]1[CH:14]=[CH:13][N:12]=[C:11]([CH2:10][S:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:16]=1[CH3:17]
Reactant: Cc1c(SCCCCl)ccnc1CCl
Reactant: Sc1ccncc1
Agent: Cl
Solvent: CC(C)O
Product: Cc1c(SCCCCl)ccnc1CSc1ccncc1

Procedure:
According to the procedure described in Example A1., reaction of 4-mercaptopyridine with 2-chloromethyl-4-(3-chloropropylthio)-3-methylpyridine hydrochloride in isopropanol gives a hydrochloride of the title compound as a colorless solid. After dissolving in water, a pH of 10 is adjusted, the mixture is extracted 2× with dichloromethane, the organic phases are washed with sodium carbonate solution and dried (magnesium sulfate), the solvent is concentrated on a rotary evaporator and the residue is crystallized from dichloromethane/diisopropyl ether. The title compound is obtained as a colorless solid; Yield 78of theory; m.p. 88-91° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:18][C:17](=[O:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH3:20][O:21]C1C(OC)=CC=CC=1C=O>>[CH3:1][O:2][C:3]1[C:8]([O:21][CH3:20])=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:18][C:17](=[O:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: COc1cccc(C=O)c1OC
Reactant: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Product: COc1cccc(-c2nc3ccccc3c(=O)[nH]2)c1OC
Yield: 86 %

Procedure:
According to the preparation of 42, 2,3-dimethoxybenzaldehyde (36) (1.2 g, 7.3 mmol) was used to afford 45 (1.8 g, 86.0%) as pale yellow needles.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]2[C@@H:17]2[CH2:19][C@H:18]2[CH:20]=[N:21]O)=[N:9]1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:7][N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]2[C@@H:17]2[CH2:19][C@H:18]2[CH2:20][NH2:21])=[N:9]1
Reactant: Cn1cc2c([C@@H]3C[C@H]3C=NO)cccc2n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc2c([C@@H]3C[C@H]3CN)cccc2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a suspension of lithium aluminum hydride (319 mg, 8.61 mmol) in tetrahydrofuran (17 mL) was added a solution of trans-2-(2-methyl-2H-indazol-4-yl)cyclopropanecarbaldehyde oxime (349 mg, 1.62 mmol) in tetrahydrofuran (17 mL) at room temperature, and the mixture was stirred at 60° C. for 1 hr. Sodium sulfate decahydrate (3.5 g) was added under ice-cooling, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give the title compound (325 mg, yield 99%).
Reaction SMILES: [CH2:1]=[CH2:2].[C:3]1([CH3:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[CH2:1]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:9])[CH3:2]
Reactant: Cc1ccccc1
Reactant: C=C
Product: CCc1ccccc1C

Procedure:
In a manner similar to the preceding examples, 3.25 grams of HZSM-5 but having a crystallite size of about 2 microns was mixed with 1.75 grams of alumina binder and extruded to produce a 1/16 inch cylindrical particle. The extrudate with a volume of 8.5 ml. was diluted with 4 volumes of low surface area quartz and tested for its ability to alkylate toluene with ethylene to yield ethyltoluene. The conditions of reaction and results are shown in Table III below.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[C:9]([O:14][CH3:15])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:16](OCC)=[O:17])[CH:5]=1)[CH3:2].CCOCC.CC(C[AlH]CC(C)C)C>CCOC(C)=O>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[C:9]([O:14][CH3:15])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([CH2:16][OH:17])[CH:5]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(OCC)c2cccc(OC)c2c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOc1cc(CO)cc2c(OC)cccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.9 %

Procedure:
To a nitrogen flushed 100 mL round bottom flask were added ethyl 4-ethoxy-8-methoxynaphthalene-2-carboxylate (0.19 g, 0.69 mmol) and dry ether (10 mL). DIBAL (1.7 mL, 1 M in toluene) was added. The reaction mixture was stirred at room temperature for 5 minutes and was then diluted with EtOAc (20 mL). Wet silica gel (10 g silica gel/0.5 mL water) was added. The resulting mixture was stirred for 10 minutes and then filtered and the filtrate was concentrated. The crude product was purified on a silica gel column eluting with a gradient of 100% hexanes to 40% EtOAc/hexanes to give the title intermediate (136 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) and 4-fluorobenzene boronic acid according to the general procedure B. Obtained as a yellow solid (1.08 g).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[Br:15]CCCCCCCCCCCCBr>Br>[Br:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13]
Reactant: BrCCCCCCCCCCCCBr
Reactant: OCCCCCCCCCCCCO
Agent: Br
Product: OCCCCCCCCCCCCBr

Procedure:
1,12-Dodecanediol (50 g, 0.25 mol) in hydrogen bromide 48% (220 ml) was continuously extracted with petroleum ether (b.p. 80-100° C.) (300 ml) for 18 hours. The solvent was evaporated under reduced pressure and the crude oil obtained was filtered through a pad of silica gel. Elution with petroleum ether (b.p. 40-60° C.) gave a colourless fraction containing 1,12-dibromododecane. The silica gel was then eluted with acetone to give the title compound as a pale yellow oil after evaporation of the solvent. The title compound crystallised upon cooling and was recrystallised from petroleum ether (b.p. 40-60° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25](I)=[CH:24][C:23]=3[F:29])[C:15]3=[CH:16][N:17]=[CH:18][CH:19]=[C:14]3[CH:13]=2)=[O:11])[CH2:4][O:3]1.C[Si]([C:35]#[CH:36])(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>N1CCCCC1.C(OCC)(=O)C.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1([CH3:30])[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:35]#[CH:36])=[CH:24][C:23]=3[F:29])[C:15]3=[CH:16][N:17]=[CH:18][CH:19]=[C:14]3[CH:13]=2)=[O:11])[CH2:4][O:3]1
Reactant: CC1(C)OC[C@H](CONC(=O)c2cc3ccncc3n2Cc2ccc(I)cc2F)O1
Reactant: C#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: C#Cc1ccc(Cn2c(C(=O)NOC[C@H]3COC(C)(C)O3)cc3ccncc32)c(F)c1
Yield: 64.4 %

Procedure:
Palladium (II) acetate (1.5 mg, 5 μmol) was added to a mixture of 1-(2-fluoro-4-iodo-benzyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ((R)-2,2-dimethyl-[1,3]-dioxolan-4-ylmethoxy)-amide (55 mg, 0.11 mmol), trimethylsilylacetylene (138 μl, 1.0 mmol) and triphenylphosphine (3 mg, 10 μmol) in piperidine (0.5 ml). The resultant mixture was heated at 150° C. under microwave irradiation for 10 seconds. The reaction mixture was diluted with ethyl acetate (35 ml) and washed sequentially with water (10 ml), then brine (10 ml). The organic layer was isolated, dried over magnesium sulphate and concentrated in vacuo to provide a residue. The residue was dissolved in methanol (5 ml) to which potassium carbonate (29 mg, 0.21 mmol) was added, and the resultant suspension was stirred at room temperature for 2 hours. The reaction mixture was filtered, concentrated in vacuo, and then partitioned between ethyl acetate (25 ml) and water (20 ml). The organic layer was isolated, dried over magnesium sulphate and concentrated in vacuo to provide a residue. Purification by flash chromatography (Si-SPE, dichloromethane:ethyl acetate, 100:0 to 70:30 to 40:60 to 0:100) afforded the title compound as a yellow solid (30 mg, 68%). LCMS (method B): RT=2.21 min, (M−H)−=422, (M+H)+=424.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C1COCC1.CCCCCCC.CCOCC.N.[N:27]1[S:31][N:30]=[C:29]2[CH:32]=[C:33]([CH2:36][C@H:37]([CH3:52])[C:38](N([C@H](C)[C@H](O)C3C=CC=CC=3)C)=[O:39])[CH:34]=[CH:35][C:28]=12.Cl>C1COCC1>[N:27]1[S:31][N:30]=[C:29]2[CH:32]=[C:33]([CH2:36][C@H:37]([CH3:52])[CH2:38][OH:39])[CH:34]=[CH:35][C:28]=12
Reactant: C[C@H]([C@H](O)c1ccccc1)N(C)C(=O)[C@@H](C)Cc1ccc2nsnc2c1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: N
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@H](CO)Cc1ccc2nsnc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2M LDA in THF/heptane/Et2O (147 ml, 0.294 mol) is diluted with 415 ml THF and cooled to 0°. At 5° to 10°, BH3.NH3 (10.05 g, 0.293 mol) is added portionwise. The solution is stirred at 0° for 15 minutes, at room temperature for 15 minutes and then recooled to 0°. Then, a solution of (S)-3-benzo[1,2,5]thiadiazol-5-yl-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl]-2,N-dimethyl-propionamide (27.2 g, 0.0736 mol) in THF (120 ml) is added dropwise over 30 minutes. The dark red solution is stirred at 0° for 3 h. 2 N HCl (700 ml) is added at 0° and the mixture stirred at this temperature for 30 minutes. Extraction with EtOAc (400 ml and 200 ml), washing of the organic phases with brine, drying with Na2SO4 and evaporation afford the crude product as a yellow-brown oil. MPLC purification (silicagel, 1 kg, EtOAc/hexane 2:1) yield pure (S)-3-Benzo[1,2,5]thiadiazol-5-yl-2-methyl-propan-1-ol as a yellow oil. ee=93.3% (HPLC on chiral stat. phase). TLC (silicagel, EtOAc/hexanes 2:1): rf 0.6.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:12]O.P(Br)(Br)[Br:15]>ClCCl>[Br:15][CH2:12][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[Cl:1])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: OCc1cnc2ccccc2c1Cl
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Clc1c(CBr)cnc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
To a solution of (4-chloroquinolin-3-yl)methanol (1.0 mg, 5.2 mmol) in anhydrous dichloromethane (50 mL) was added dropwise phosphorus tribromide (1.0 mL, 11.2 mmol). The mixture was stirred at room temperature for 3 hours. Dichloromethane was evaporated. Water (20 mL) was added. The mixture was treated slowly with a saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane (2×30 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo, affording 3-(bromomethyl)-4-chloroquinoline (982 mg, 74% yield). The product was used without further purification.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][N:6]([C:8]([NH:10][CH2:11][CH3:12])=[NH:9])[N:5]=[CH:4]1)[CH3:2].CCN(C(C)C)C(C)C.Cl[S:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>C(Cl)Cl>[CH2:11]([NH:10][C:8](=[N:9][S:23]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[CH:33][CH:34]=1)(=[O:25])=[O:24])[N:6]1[CH2:7][CH:3]([CH2:1][CH3:2])[CH:4]=[N:5]1)[CH3:12]
Reactant: CCNC(=N)N1CC(CC)C=N1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=NS(=O)(=O)c1ccc(C(=O)O)cc1)N1CC(CC)C=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.5 %

Procedure:
Under N2 atmosphere, 2.27 g 4,N-diethyl-4,5-dihydro-pyrazole-1-carboxamidine was dissolved in 30 mL dry DCM, and 5.17 ml DiPEA and 2.98 g of 4-(chlorosulfonyl)benzoic acid were added. The mixture was stirred overnight at room temperature and evaporated to dryness. The residue was purified by flash chromatography (first column with DCM/MeOH/NH4OH 92:7.5:0.5; second column with DCM/MeOH/Acetic acid 92:7.5:0.5) to yield 0.26 g (4%) of product (mono-DiPEA salt) as an off-white amorphous powder. 1H NMR (400 MHz, CDCl3) δ 0.98 (t, J=7.4 Hz, 3H), 1.27 (t, J=7.2 Hz, 3H), 1.53-1.81 (m, 2H), 3.15-3.30 (broad peak, 1H), 3.43-3.66 (broad peak, 3H), 4.01-4.20 (broad peak, 1H), 6.97 (br. s., 1H), 7.90 (d, J=8.1 Hz, 2H), 8.14 (d, J=8.1 Hz, 2H), 9.69 (br. s., 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.Cl.[NH2:13][CH:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O.C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:13][CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:7]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: Cc1ccc(C(=O)O)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)c1ccc(C)c(F)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of 10.1 g of 3-fluoro-4-methylbenzoic acid and 15.2 g of diethyl aminomalonate hydrochloride in 200 ml of N,N-dimethylformamide, 9.7 g of 1-hydroxybenzotriazole, 23 ml of triethylamine and 13.8 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added sequentially, and stirred for 1 hour at room temperature. After addition of water to the reaction solution, the mixture was extracted with ethyl acetate. The extract was washed with water, 10% hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution sequentially and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was crystallized by addition of isopropyl ether to provide 15.1 g of the objective compound as colorless crystals. M.p. 102–103° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9]C)[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][C:35]4([CH2:39][N:40]5[CH:44]=[C:43]([B:45]6[O:49][C:48]([CH3:51])([CH3:50])[C:47]([CH3:53])([CH3:52])[O:46]6)[CH:42]=[N:41]5)COC4)[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:57][CH3:58])[N:14]=2)=[CH:4][CH:3]=1.BrC1N=C(C(=O)N[O:68][CH3:69])C(NC2C(C(F)(F)F)=CN=C(NC3C=CC(CP(=O)(O)OCC)=CC=3OC)N=2)=CC=1.CC1(C)C(C)(C)OB(C2C=NN(CCCO)C=2)O1>>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][O:68][CH3:69])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:21])([F:22])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][CH2:35][CH2:39][N:40]4[CH:44]=[C:43]([B:45]5[O:46][C:47]([CH3:52])([CH3:53])[C:48]([CH3:50])([CH3:51])[O:49]5)[CH:42]=[N:41]4)[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:57][CH3:58])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NOC)n2)c(OC)c1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1)OCC1(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)COC1
Agent: CC1(C)OB(c2cnn(CCCO)c2)OC1(C)C
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NOC)n2)c(OC)c1)OCCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1

Procedure:
Racemic Compound 46A was prepared analogously to Compound 44A using ethyl hydrogen (4-{[4-{[6-bromo-2-(methoxycarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound KS11B, 50.0 mg, 0.0787 mmol) and 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-1-ol (Compound 3E, 20.8 mg, 0.0826 mmol) to afford 45 mg of the desired material (28%). MS (ESI): m/z=869.25/871.23 [M+H]+. UPLC: tR=1.48 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[C:22]([O:29][CH3:30])[CH:21]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][C:22]=3[O:29][CH3:30])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1cc(F)ccc1B(O)O
Product: CCCNC(=O)c1nnc2c(-c3ccc(F)cc3OC)cccc2c1N
Yield: 83.2 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 4-fluoro-2-methoxy-phenylboronic acid (170 mg, 1.000 mmol) were reacted to afford the title compound (143 mg, 83% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.55 (br, 1H), 7.87 (m, 1H), 7.74-7.67 (m, 2H), 7.34-7.27 (m, 1H), 6.83-6.72 (m, 2H), 3.69 (s, 3H), 3.45 (apparent quartet, J=7.0 Hz, 2H), 1.65 (apparent sextet, J=7.0 Hz, 2H), 0.99 (t, 3H, J=7.0 Hz). MS APCI, m/z=355 (M+H). HPLC 1.66 min.