Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:43])[CH:6]([O:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:25][NH:26][C:27]([C:29]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[O:31][C:30]=3[CH2:38][CH2:39][CH2:40][CH3:41])=[O:28])[CH:21]=2)[C:16]=1[Br:42])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.Cl>CO>[Br:42][C:16]1[C:17]2[C:22](=[CH:21][C:20]([CH2:25][NH:26][C:27]([C:29]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[O:31][C:30]=3[CH2:38][CH2:39][CH2:40][CH3:41])=[O:28])=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[O:14][CH:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:5]([OH:43])=[O:4]
Reactant: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(Br)c(OC(Cc3ccccc3)C(=O)OC)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(Br)c(OC(Cc3ccccc3)C(=O)O)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
1 N Sodium hydroxide (220 μL, 0.22 mmol) was added under nitrogen to a solution of 2-(1-bromo-6-{[(2-butyl-benzofuran-3-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid methyl ester (107 mg, 0.17 mmol), prepared in the previous step, in 40 mL of methanol plus 10 mL of water at room temperature. After the addition the reaction was stirred at room temperature overnight. By TLC starting material remained. Additional quantities of 1 N NaOH were added until the reaction was complete by TLC. The reaction was acidified by the addition of 1 N HCl and then concentrated under reduced pressure to remove the methanol. The solid formed was collected by filtration and dried under reduced pressure to give the title compound (61 mg, 58%) as a white solid, mp 125-130° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:13]1[N:14]=[N:15][CH:16]=[C:17]2[C:21]([CH3:22])=[C:20]([CH3:23])[N:19]([CH2:24][C@H:25]3[CH2:27][C@@H:26]3[CH3:28])[C:18]=12.O>O1CCCC1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][C:13]2[N:14]=[N:15][CH:16]=[C:17]3[C:21]([CH3:22])=[C:20]([CH3:23])[N:19]([CH2:24][C@H:25]4[CH2:27][C@@H:26]4[CH3:28])[C:18]=23)=[CH:4][CH:3]=1
Reactant: Cc1c(C)n(C[C@H]2C[C@@H]2C)c2c(Cl)nncc12
Reactant: OCc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C)n(C[C@H]2C[C@@H]2C)c2c(OCc3ccc(F)cc3)nncc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
A solution of p-fluorobenzyl alcohol (1.45 g, 11.5 mmol) in tetrahydrofuran (2 ml) was added dropwise to a solution of sodium hydride (0.26 g, 10.8 mmol) in tetrahydrofuran (6 ml) and the mixture was stirred at room temperature for 30 minutes. A solution of 7-chloro-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazine (2.50 g, 10.0 mmol) in tetrahydrofuran (13 ml) was added dropwise to the reaction mixture and the mixture was heated under reflux for 3 hours. After this time the reaction mixture was poured into iced water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated in vacuo. Hexane was added to the residue, and the precipitate was collected by filtration and then recrystallized from a mixture of ethyl acetate and hexane to afford the title compound (2.25 g, 66.4%) as pale brown crystals.
Reaction SMILES: Cl([O-])=O.[Na+].[F:5][CH:6]([F:22])[O:7][C:8]1[CH:9]=[CH:10][C:11]([CH:20]=[O:21])=[C:12]2[C:16]=1[O:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13]2.S(N)(=O)(=O)[OH:24]>O.C(O)(=O)C>[F:22][CH:6]([F:5])[O:7][C:8]1[CH:9]=[CH:10][C:11]([C:20]([OH:24])=[O:21])=[C:12]2[C:16]=1[O:15][C:14]([CH:17]([CH3:18])[CH3:19])=[CH:13]2
Reactant: NS(=O)(=O)O
Reactant: CC(C)c1cc2c(C=O)ccc(OC(F)F)c2o1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1cc2c(C(=O)O)ccc(OC(F)F)c2o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 0.88 g of sodium chlorite in 5 ml of water is added dropwise to 1.6 g of 7-difluoromethoxy-2-(1-methylethyl)benzofuran-4-carbaldehyde and 0.83 g of amidosulfuric acid, dissolved in 15 ml of glacial acetic acid, such that the internal temperature is kept between 15 and 20° C. The mixture is stirred for a further 1 h and then poured into 150 ml of ice water, and the precipitate formed is filtered off with suction and washed with water until acid-free. For purification, the crude product is dissolved in halfconcentrated, aqueous ammonia, and the aqueous solution is extracted with toluene and acidified with 2 N hydrochloric acid to pH 1-2. The precipitate formed is filtered off with suction, washed with water until acid-free and dried in vacuo: m.p. 169° C.
Reaction SMILES: [B:1](OCCCC)([O:7]CCCC)[O:2]CCCC.C([O:19][CH:20](OCC)[C:21]1[CH:26]=[CH:25][C:24]([Mg]Br)=[CH:23][CH:22]=1)C.C(OC)(C)(C)C.S(=O)(=O)(O)O>O1CCCC1>[CH:20]([C:21]1[CH:26]=[CH:25][C:24]([B:1]([OH:7])[OH:2])=[CH:23][CH:22]=1)=[O:19]
Reactant: CCOC(OCC)c1ccc([Mg]Br)cc1
Reactant: CCCCOB(OCCCC)OCCCC
Agent: O=S(=O)(O)O
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: O=Cc1ccc(B(O)O)cc1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
Using a method based on that in Liebigs Ann. 1995, 1253-1257, a solution of 120 g of tri-n-butyl borate in 250 g of dry tetrahydrofuran was placed under nitrogen in a dried 2 l flask fitted with a dropping funnel and cooled to -50° C. 535 g of a 26.5% strength solution of 4-diethoxymethylphenylmagnesium bromide in THF are then added dropwise at such a rate that the internal temperature does not exceed −40 to −50° C. The mixture is subsequently stirred at −50° C for another 1 hour. 1 l of methyl t-butyl ether (MTBE) is subsequently added and the mixture is hydrolyzed at 5-10° C. using 650 g of 1M sulfuric acid. The aqueous phase was separated off and extracted three times with 500 ml each time of methyl t-butyl ether. The solvent was distilled off under reduced pressure and the crude boronic acid was once again taken up in 0.5 l of water and 185 ml of 5N aqueous potassium hydroxide (pH 14) at 5° C. The aqueous phase was extracted once with 250 ml of MTBE and subsequently, at 5° C., brought to a pH of 1 using 400 ml of 1M sulfuric acid. The precipitate was filtered off, washed twice with 150 ml of ice water and dried. This gives 66.1 g of 4-formylphenylboronic acid (88% of theory) comprising, according to HPLC, 89% of 4-formylphenylboronic acid, 4% of 4-carboxyphenylboronic acid, 3.8% of 4-hydroxymethylphenylboronic acid.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:14]=[CH:15][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>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>[CH3:21][O:20][C:18](=[O:19])[CH2:17][C:13]1[CH:12]=[C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)Cc1cccc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cccc(-c2ccccc2)c1
Yield: 78.8 %

Procedure:
A mixture of phenylboronic acid (1.000 g, 8.20 mmol), methyl 3-bromophenylacetate (1.691 g, 7.38 mmol), Na2CO3 (1.738 g, 16.4 mmol), tetrakis(triphenylphosphine)palladium(0) (0.474 g, 0.41 mmol), toluene (30 mL), and water (5 mL) was heated under reflux for 20 h. The reaction mixture was diluted with water (20 mL) and the volatiles were removed in vacuo. The aqueous solution was washed with EtOAc (4×20 mL). The organic solutions were combined, washed with 1N NaOH (15 mL) followed by water (15 mL). The organic solution was dried (MgSO4), filtered and concentrated in vacuo. Purification by medium pressure chromatography (79:1 hexanes:EtOAc to 39:1 hexanes:EtOAc) provided biphenyl-3-yl-acetic acid methyl ester (1.316 g).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:8]=2[CH2:9][NH:10]C(=O)OC(C)(C)C)=[O:6])[CH2:3][CH2:2]1.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>C(Cl)Cl>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[NH2:10][CH2:9][C:8]1[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:7]=1[C:5]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:6]
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)cc1C(=O)NC1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ccc(F)cc1C(=O)NC1CC1
Yield: 100 %

Procedure:
A solution of tert-butyl 2-(cyclopropylcarbamoyl)-4-fluorobenzylcarbamate (130 mg, 0.42 mmol), prepared according to literature methods, in CH2Cl2 (5 mL) was stirred with trifluoroacetic acid (3 mL) at room temperature for 10 min, then concentrated in vacuo to give 140 mg (Yield 100%) of the title compound as a foam: 1H NMR (DMSO-d6, 300 MHz) δ ppm: 0.62 (2H, m, CH2), 0.73 (2H, m, CH2), 2.86 (1H, m, CH), 4.02-4.07 (2H, ABq, NCH2), 7.46 (2H, m, Ar—Hs), 7.58 (1H, m, Ar—H), 8.11 (3H, br, NH3), 8.81 (1H, d, J=4.4 Hz, NH); LC/MS m/z 209 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:13][C:14]#[N:15])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8]C)=[O:7]>CO>[C:14]([CH2:13][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7])#[N:15]
Reactant: COC(=O)c1cccc(OC)c1CC#N
Solvent: CO
Product: COc1cccc(C(=O)O)c1CC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 86847.4 %

Procedure:
Into a 500 mL 3-neck round bottom flask was added 10 g (61.75 mmol) of 2-bromomethyl, 3-methoxy methyl benzoate, 4.0 g (81.6 mmol) of NaCN, 0.30 g (2 mmol) of NaI, 100 mL of CH3CN, and 50 mL of DMF. The reaction mixture was heated and refluxed for 10 hours. The precipitate (NaBr) was filtered off, and the solution was concentrated on an evaporator. 300 mL of water and 200 mL of ether were added and then shaken in a separatory funnel. The water was extracted twice with 100 mL of ether. The ether fractions were dried over MgSO4, and concentrated to yield methyl 3-methoxy-2-cyanomethylbenzoate (95-100% yield). This ester (0.053 mmol, 10.51 g) was stirred vigorously in 100 mL of CH3OH. Ba(OH)2H2O (0.079 mmol, 14.97 g) was added and the mixture stirred at room temperature overnight. The CH3OH was removed on a rotary evaporator. 150 mL of water, 200 mL of CH2Cl2, and 50 mL of 6N HCl were added, and then stirred in a flask to dissolve all residues. The mixture was transferred to a separatory funnel, acidified with 6N HCl to pH 1-2. The CH2Cl2 phase was separated and the aqueous phase extracted twice with 50 mL of CH2Cl2. The CH2Cl2 extracts were combined, dried over MgSO4 and charcoal, filtered, and evaporated to yield 8.8 g of a white solid, 2-cyanomethyl-3-methoxybenzoic acid, (87%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15](I)[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.[Cu][C:28]#[N:29]>O1CCCC1.C(OCC)(=O)C.[Cu]I>[Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([C:28]#[N:29])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: N#C[Cu]
Reactant: Cc1cc(I)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12

Procedure:
To a solution of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-iodo-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the benzoxazinone product of Step E) (600 mg, 1.1 mmol) in tetrahydrofuran (15 mL) was added copper(I) iodide (126 mg, 0.66 mmol), tetrakis(triphenyphosphine)palladium(0) (382 mg, 0.33 mmol) and copper(I) cyanide (800 mg, 8.8 mmol) sequentially at room temperature. The reaction mixture was then heated at reflux overnight. The reaction turned black in color, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The reaction mixture was diluted with ethyl acetate (20 mL) and filtered through Celite®, followed by washing three times with 10% sodium bicarbonate solution and once with brine. The organic extract was dried (MgSO4) and concentrated under reduced pressure to afford 440 mg of the title compound as a crude yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:3]=1[CH3:20].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][C:28]=2[NH2:29])[CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[N:24]1([C:27]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:30][C:28]=2[NH:29][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:3]=2[CH3:20])[CH2:25][CH2:26][O:21][CH2:22][CH2:23]1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to Procedure H using 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (39.8 mg, 0.137 mmol) and 2,5-dimorpholinoaniline in toluene to give N-(2,5-di-4-morpholinylphenyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (CDCl3) δ ppm 8.71 (1H, d, J=4.7 Hz), 8.15 (1H, d, J=10.2 Hz), 7.82-7.97 (2H, m), 7.64 (1H, d, J=9.4 Hz), 7.38 (1H, ddd, J=6.7, 4.7, 2.3 Hz), 7.10 (1H, d, J=8.6 Hz), 6.99 (1H, ddd, J=13.3, 8.6, 2.7 Hz), 6.48 (1H, dd, J=8.4, 2.5 Hz), 6.22 (1H, d, J=2.3 Hz), 3.90 (4H, t, J=4.3 Hz), 3.76-3.85 (4H, m), 3.05-3.19 (4H, m), 2.92 (4H, br. s.), 2.22 (3H, s). Mass Spectrum (ESI) m/e=518.2 (M+1).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[N:7]=1)C.[Li+].[BH4-].O.Cl>C1COCC1>[Cl:12][C:8]1[N:7]=[C:6]([CH2:5][CH2:4][OH:3])[CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)Cc1cccc(Cl)n1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCc1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.1 %

Procedure:
To a solution of ethyl(6-chloro-2-pyridinyl)acetate (Example 469, 5.00 g, 25 mmol) in THF (50 mL) was added LiBH4 (13.0 mL, 25.0 mmol, 2M solution in THF) at 0° C. The mixture was stirred at rt for 18 h, then water was slowly added [strong gaseous evolution] followed by HCl (10 mL, 1N aqueous solution). The mixture was extracted with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and then concentrated under reduced pressure. The residue was purified using a short pad of silica gel (4:1 hexanes/EtOAc) to give the product (3.00 g, 76%) as a light-yellow oil which solidified upon standing. 1H NMR (400 MHz, CDCl3) δ 2.97 (t, 2H), 3.98 (t, 2H), 7.10 (dd, 2H), 7.54 (t, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.CC1C=CC(S(O[CH2:20][CH2:21][CH2:22][NH:23][C:24]2[C:25](=[O:41])[N:26]([C:37]([CH3:40])([CH3:39])[CH3:38])[S:27](=[O:36])(=[O:35])[C:28]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=O)=O)=CC=1>>[C:37]([N:26]1[C:25](=[O:41])[C:24]([NH:23][CH2:22][CH2:21][CH2:20][O:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[C:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[S:27]1(=[O:35])=[O:36])([CH3:38])([CH3:39])[CH3:40]
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Reactant: Oc1cccc(Cl)c1
Product: CC(C)(C)N1C(=O)C(NCCCOc2cccc(Cl)c2)=C(c2ccccc2)S1(=O)=O
Yield: 72 %

Procedure:
The title compound was prepared as described for Example 12 from 3-chlorophenol and 3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate with a reaction time of 15 mins. The reaction mixture was evaporated and purified by silica gel column chromatography (Horizons Biotage) using 15% EtOAc in petroleum ether 40-60° C. as eluent to give the title compound (0.079 g, 72%). 1H NMR (500 MHz CDCl3): δ 7.54-7.50 (m, 2H), 7.46-7.40 (m, 3H), 7.20 (t, 1H), 6.95 (d, 1H), 6.84 (s, 1H), 6.75 (dd, 1H), 5.67 (t, 1H), 3.86 (t, 1H), 3.11-3.04 (m, 2H), 1.86-1.80 (m, 2H), 1.75 (s, 9H), 13C NMR (125 MHz CDCl3): δ 159.8, 159.3, 135.3, 135.1, 131.8, 130.5, 129.8, 128.8, 125.3, 121.5, 115.0, 113.2, 107.4, 66.2, 61.7, 42.4, 28.9, 27.8: Mass Spectrum M+H+ 449.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[C:18]([CH3:19])[C:11]=12.[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[C:23]([NH2:28])[N:22]=1.Cl.[OH-].[Na+]>O>[Cl:20][C:21]1[N:22]=[C:23]([NH2:28])[N:24]=[C:25]([NH:8][C:6]2[CH:5]=[CH:4][C:3]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:16][CH:17]=[C:18]([CH3:19])[C:11]=34)=[C:2]([F:1])[CH:7]=2)[CH:26]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Cc1c[nH]c2nccc(Nc3ccc(N)cc3F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c[nH]c2nccc(Nc3ccc(Nc4cc(Cl)nc(N)n4)cc3F)c12
Temperature: 100 °C

Procedure:
19 mg (70 μmol) of 2-fluoro-N1-(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzene-1,4-diamine and 17 mg (10 μmol) of 4,6-dichloropyrimidine-2-amine are suspended in 3.5 ml of water. 100 μI of 1 M hydrochloric acid are added, and the mixture is heated at 100° C. overnight. Using 1N aqueous sodium hydroxide solution, the suspension is then adjusted to pH 10, resulting in the precipitation of crystals. The solid is filtered off and washed with water. The crude product is purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol (7M ammonia) 100:1 to 10:1).
Reaction SMILES: [CH2:1]([C:3]1([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[CH2:6][O:5][CH2:4]1)[CH3:2].C([Li])CCC.C(O[B:29]1[O:33][C:32]([CH3:35])([CH3:34])[C:31]([CH3:37])([CH3:36])[O:30]1)(C)C>C1COCC1>[CH2:1]([C:3]1([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[S:16][C:17]([B:29]3[O:33][C:32]([CH3:35])([CH3:34])[C:31]([CH3:37])([CH3:36])[O:30]3)=[CH:18][CH:19]=2)[CH2:4][O:5][CH2:6]1)[CH3:2]
Reactant: CCC1(COCCCCCCc2cccs2)COC1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC1(COCCCCCCc2ccc(B3OC(C)(C)C(C)(C)O3)s2)COC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
To a stirred solution of 3-ethyl-3-(6-thiophen-2-yl-hexyloxymethyl)-oxetane (6.0 g, 21.28 mmol) in dry THF (70 ml) is added n-butyllithium (2.5 M in hexanes, 8.10 ml, 21.28 mmol) dropwise at −78° C. under nitrogen. After complete addition, the mixture is allowed to warm to room temperature, with stirring, over 2 h, followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.96 g, 21.28 mmol). The resultant mixture is stirred overnight at room temperature. The reaction is quenched with water, and the reaction mixture is extracted with ethyl acetate (3×70 ml). The combined organic extracts are washed with water, brine, and dried over sodium sulphate. The solvent is removed under reduced pressure and the residue is purified by column chromatography on silica, eluting with petroleum ether/ethyl acetate (9:1), to give a yellow oil (6.28 g, 72%). 1H NMR (300 MHz, CDCl3): δ (ppm) 7.45 (d, J=3.4 Hz, 1H, Ar—H), 6.85 (d, J=3.4 Hz, 1H, Ar—H), 4.44 (d, J=5.8 Hz, 2H, OCH2), 4.36 (d, J=5.8 Hz, 2H, OCH2), 3.51 (s, 2H, OCH2), 3.45 (t, J=6.4 Hz, 2H, OCH2), 2.83 (t, J=7.6 Hz 2H, ArCH2), 1.32-1.77 (m, 22H, CH2 and CH3), 0.88 (t, J=7.4 Hz, 3H, CH3); δ (ppm) 153.5 (quat.), 145.6 (quat.), 137.3 (CH), 125.9 (CH), 83.9 (quat.), 78.6 (OCH2), 73.4 (OCH2), 71.5 (OCH2), 43.4 (quat.), 31.6 (CH2), 30.1 (CH2), 29.4 (CH2), 28.8 (CH2), 26.8 (CH2), 25.9 (CH2), 24.8 (CH3), 8.2 (CH3); MS (m/e): 408 (M+, 0.5%), 223 (27), 165 (30), 141 (35), 123 (100), 97 (52).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH2:10])[N:5]=1.Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O>[NH2:10][C:6]1[N:5]=[C:4]([CH:3]=[O:2])[CH:9]=[CH:8][N:7]=1
Reactant: COC(OC)c1ccnc(N)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Nc1nccc(C=O)n1
Temperature: 25 °C
Yield: 37.4 %

Procedure:
A solution of 2.5 g (15 mmol, 1.0 eq.) 2-aminopyrimidine-4-carboxaldehyde dimethylacetal in 16 ml (45 mmol, 3 eq.) of 3M HCl was heated at 48° C. for 14 h. The mixture was cooled to r.t. and layered with 50 mL of EtOAc. The aqueous layer was neutralized with NaHCO3 and then extracted with EtOAc (5×50 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo afford 0.69 g (37%) of 2-aminopyrimidine-4-carboxaldehyde.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:14])[CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6][CH:7]=1.I[CH3:16]>CC(C)=O>[CH3:16][O:1][C:2]1[C:3](=[O:14])[CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6][CH:7]=1
Reactant: O=c1cc(-c2ccccc2)occ1O
Reactant: CI
Solvent: CC(C)=O
Product: COc1coc(-c2ccccc2)cc1=O
Temperature: 60 °C
Yield: 93 %

Procedure:
To a solution of crude 5-hydroxy-2-phenyl-4H-pyran-4-one (0.4 mmol) in acetone (10.9 mL) is added iodomethane (0.7 mL, 1 1.3 mmol) and the reaction mixture was heated at 60° C. for 2 h. After being cooled to room temperature, the reaction was concentrated under reduced pressure and diluted with CHCl3 (10 mL) and water (10 mL). The layers were separated and the organic fraction washed with sat. aq. NaCl, dried (Na2SO4), and concentrated under reduced pressure to provide (93%) of 5-methoxy-2-phenyl-4H-pyran-4-one as tan crystals which were used in the subsequent step without further purification. LC/MS (M+H)+ 203.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[CH2:20]([N:27]1[CH2:31][CH2:30][CH2:29][C:28]1=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])(O)=O.[Na+]>C1COCC1.C(O)(=O)C>[CH2:20]([N:27]1[CH2:31][CH2:30][CH:29]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CCCN1Cc1ccccc1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: c1ccc(CN2CCC(N3CCCC3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.82 g (18.0 mmol) NaBH(OAc)3 are added to a solution of 1.23 mL (15.0 mmol) pyrrolidine and 2.41 mL (15.0 mmol) N-benzylpyrrolidinone in 100 mL THF and acidified with 2 mL acetic acid. The reaction is stirred overnight at RT. The reaction solution is combined with 200 mL saturated NaHCO3 solution and extracted twice with 200 mL EtOAc. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The purification is carried out by column chromatography on silica gel (EtOAc/MeOH/NH3 8:2:0.2).
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl[C:11](Cl)([O:13][C:14](=[O:20])OC(Cl)(Cl)Cl)Cl.[F:22][C:23]1[CH:30]=[C:29]([C:31]2[N:32]=[C:33]([NH:36][C:37](C)([CH3:40])[CH2:38]O)[S:34][CH:35]=2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]>C(Cl)Cl>[CH3:38][C:37]1([CH3:40])[CH2:11][O:13][C:14](=[O:20])[N:36]1[C:33]1[S:34][CH:35]=[C:31]([C:29]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([F:22])[CH:30]=2)[N:32]=1
Reactant: CC(C)(CO)Nc1nc(-c2ccc(C#N)c(F)c2)cs1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)COC(=O)N1c1nc(-c2ccc(C#N)c(F)c2)cs1
Temperature: 0 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
N,N-diisopropylethylamine (1.4 mL, 7.9 mmol) and triphosgene (1.2 g, 3.9 mmol) in 20 mL of dry methylene chloride were added to a solution of 2-fluoro-4-{2-[(2-hydroxy-1,1-dimethylethyl)amino]-1,3-thiazol-4-yl}benzonitrile (955 mg, 3.3 mmol), prepared in the previous step, in 50 mL of dry methylene chloride at 0° C. The reaction was stirred at 0° C. for 3 h and then allowed to warm to room temperature. The reaction was washed with 1×100 mL of 2N HCl. The aqueous layer was extracted with methylene chloride (2×100 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give 1.0 g of a yellow solid. Purification of the solid on silica gel using a stepwise gradient of 5% to 40% ethyl acetate-hexane gave the title compound (450 mg, 43%) as a yellow solid, mp 204-206° C.