Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]([CH:38]=[CH:39][CH:40]=2)[C:28]([O:30]CC2C=CC=CC=2)=[O:29])O1.C(=O)([O-])[O-].[Na+].[Na+].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.CN(C)C=O>[C:10]([O:9][C:8]([NH:7][CH2:6][C:5]1[CH:15]=[CH:16][C:2]([C:25]2[CH:40]=[CH:39][CH:38]=[C:27]([C:28]([OH:30])=[O:29])[CH:26]=2)=[CH:3][CH:4]=1)=[O:14])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC1(C)OB(c2cccc(C(=O)OCc3ccccc3)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1
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: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(C(=O)O)c2)cc1
Temperature: 80 °C
Reaction time: 1.17 h
Yield: 79.8 %

Procedure:
To a mixture of tert-butyl N-(4-bromobenzyl)carbamate (0.425 g), benzyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolane-2-yl)benzoate (0.553 g), sodium carbonate (0.315 g), water (1.3 mL) and N,N-dimethylformamide (6.5 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.086 g), and the resulting mixture was stirred at 80° C. for 70 minutes. The reaction mixture was cooled to room temperature and then partitioned between ethyl acetate (35 mL) and water (15 mL). The organic layer was washed successively with water/brine (2/1, 15 mL×2) and brine (15 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a solution of the residue (1.0 g) in ethanol (7.4 mL) was added 1 mol/L aqueous sodium hydroxide (2.23 mL), and the resulting mixture was stirred at 80° C. for 80 minutes. One mol/L aqueous sodium hydroxide (2.23 mL) was added and stirring was continued for additional 2 hours. The reaction mixture was cooled to room temperature. One mol/L hydrochloric acid (4.46 mL) was added and then the whole was partitioned between ethyl acetate (35 mL) and water (10 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/2-1/2) to give 4′-(tert-butoxycarbonylaminomethyl)biphenyl-3-carboxylic acid (0.388 g). To a solution of the carboxylic acid (0.330 g) in N,N-dimethylformamide (5.0 mL) were added successively dimethylamine hydrochloride (0.123 g), diphenylphosphoryl azide (0.435 mL) and triethylamine (0.422 mL), and the resulting mixture was stirred at room temperature for 67.5 hours. One mol/L hydrochloric acid (10 mL) was added and the whole was extracted with ethyl acetate (30 mL). The organic layer was washed successively with water (10 mL), saturated aqueous sodium hydrogen carbonate (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/ethyl acetate=8/1) to give the title compound (0.246 g).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:14][O:13]1.[C:15]1([CH2:21][N:22]2[CH:27]3[CH2:28][CH2:29][CH:23]2[CH2:24][NH:25][CH2:26]3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CS(C)=O.O>[OH:13][CH:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])[CH2:14][N:25]1[CH2:26][CH:27]2[N:22]([CH2:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:23]([CH2:29][CH2:28]2)[CH2:24]1
Reactant: c1ccc(CN2C3CCC2CNC3)cc1
Reactant: Cc1c(C2CO2)ccc2c1COC2=O
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(C(O)CN2CC3CCC(C2)N3Cc2ccccc2)ccc2c1COC2=O
Temperature: 150 °C

Procedure:
A mixture of 4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one (1.0 g, 3.7 mmol) and 8-(phenylmethyl)-3,8-diazabicyclo[3.2.1]octane (748 mg, 3.68 mmol) in 2 mL DMSO was heated under microwave condition (150° C.) for 1 hr. After cooling to rt., the mixture was diluted with water (50 mL), extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine and dried over Na2SO4, then concentrated. The residue was purified by TLC (MeOH/DCM=1:15) to obtain 5-{1-hydroxy-2-[8-(phenylmethyl)-3,8-diazabicyclo [3.2.1]oct-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one. The two isomers were separated by SFC chiral chromatography to obtain two single isomers, isomer A and isomer B with the same MS m/z 393 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=2)=[N:6][CH:7]=1.[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(C)cc(-c2ncc(Br)cn2)c1
Reactant: Cc1cccc(C)c1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(C)cc(-c2ncc(-c3c(C)cccc3C)cn2)c1
Yield: 83 %

Procedure:
Then, 0.91 g of 5-bromo-2-(3,5-dimethylphenyl)pyrimidine, 1.05 g of 2,6-dimethylphenylboronic acid, 0.74 g of sodium carbonate, 0.029 g of bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), 13 mL of water, and 13 mL of acetonitrile were put into a recovery flask equipped with a reflux pipe, and the mixture was bubbled with argon for 15 minutes. This reaction container was subjected to irradiation with microwaves (2.45 GHz, 100 W) for 4 hours to be heated. Here, into the flask were further put 1.07 g of 2,6-dimethylphenylboronic acid, 0.73 g of sodium carbonate, and 0.029 g of Pd(PPh3)2Cl2, and the mixture was bubbled with argon for 15 minutes. This reaction container was subjected to irradiation with microwaves (2.45 GHz, 100 W) again for 3 hours to be heated. After that, the obtained mixture was suction-filtered with water. The obtained solid was purified by flash column chromatography using toluene and hexane as a developing solvent in a ratio of 1:1, so that Hdmppm2-dmp (abbreviation), which was the pyrimidine derivative to be produced, was obtained as a white powder in a yield of 83%. A synthesis scheme of Step 2 is shown in (i-2).
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[N:7]=[C:8]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[O:9][C:10]=1[CH3:11]>CS(C)=O>[CH:12]1([C:8]2[O:9][C:10]([CH3:11])=[C:6]([CH2:5][C:1]#[N:2])[N:7]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: [C-]#N
Reactant: Cc1oc(C2CCCCC2)nc1CCl
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1oc(C2CCCCC2)nc1CC#N
Reaction time: 2 h
Yield: 48.2 %

Procedure:
To 1.464 g of NaCN (29.88 mmol), dissolved in 20 ml of DMSO, was slowly added via dropping funnel 4.12 g of the above prepared 4-chloromethyl-2-cyclohexyl-5-methyl-oxazole (19.28 mmol) at such a rate that the internal temperature stayed at 25–30°. Stirring was continued for additional 2 h at 35°. The reaction mixture was then poured onto crashed ice/AcOEt, the organic layer washed with water, dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=8/2) gave 1.900 g of the title compound as colorless liquid.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[CH:8]2.CS([Cl:17])(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[Cl:17][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[CH:8]2
Reactant: OCc1cccc2cnccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ClCc1cccc2cnccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 0.1212 g (0.76 mmol) 15 in 8 mL CH2Cl2 at 0° C. was added 64.8 μL (0.84 mmol) methanesulfonyl chloride and 84.7 μL (0.61 mmol) triethylamine. After 3 h at 0° C., the reaction mixture was warmed to room temperature and 32.0 μL (0.23 mmol) triethylamine added. The reaction was recooled to 0° C., and 14.7 μL (0.19 mmol) methanesulfonyl chloride and 26.5 μL (0.19 mmol) triethylamine were added. After 62 h at room temperature, the reaction mixture was diluted with 25 mL CH2Cl2 and washed with 10 mL saturated NaHCO3 solution. The aqueous layer was extracted with 10 mL CH2Cl2, and the combined organic layers were washed with 10 mL brine, dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by flash chromatography (15×140 mm silica gel, 2% (10% NH40H:MeOH):CH2Cl2). Mixed fraction repurified by flash chromatography (12×75 mm silica gel, 1% (10% NH40H:MeOH):CH2Cl2) to give 16. 1H NMR (CDCl3, 400 MHz) δ 9.305 (s, 1H, ArH); 8.653 (d, 1H, J=5.85 Hz, ArH); 7.992 (d, 1H, J=8.23 Hz, ArH); 7.927 (d, 1H, J=5.94 Hz, ArH); 7.753 (d, 1H, J=7.04 Hz, ArH); 7.583 (dd, 1H, J=7.14, 8.14 Hz, ArH); 5.020 (s, 1H, ArCH2); MS (Electrospray): m/z 177.9, 179.9 (M+H, 35Cl, 37Cl).
Reaction SMILES: Cl.C([O:6][C:7]1[C:19]([F:20])=[CH:18][C:10]([C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[O:12])=[C:9]([F:21])[CH:8]=1)(C)(C)C>O1CCOCC1>[F:21][C:9]1[CH:8]=[C:7]([OH:6])[C:19]([F:20])=[CH:18][C:10]=1[C:11]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[O:12]
Reactant: CC(C)(C)Oc1cc(F)c(C(=O)NS(C)(=O)=O)cc1F
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)NC(=O)c1cc(F)c(O)cc1F
Temperature: 25 °C
Yield: 103.5 %

Procedure:
Hydrochloric acid solution in dioxane (4 M, 30 mL) was added to the 4-tert-butoxy-2,5-difluoro-N-(methylsulfonyl)benzamide (Preparation 109, 1.76 g, 5.73 mmol) and the resulting solution stirred at room temperature. After 3 hours the reaction mixture was concentrated in vacuo and the residue azeotroped repeatedly with DCM to yield the title compound as a white solid (1.49 g, 100%).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:10][C:11]([CH2:14]O)=[CH:12][N:13]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.S([Cl:27])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:27][CH2:14][C:11]1[S:10][C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)=[N:13][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2ncc(CO)s2)OCCO1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(c2ncc(CCl)s2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-5-yl]-methanol (560 mg, 2.78 mmol) in dry CH2Cl2 (5.0 mL) was treated at 0° C. with Et3N (0.50 mL, 3.60 mmol) followed by DMAP (34 mg, 0.28 mmol) and Ms-Cl (0.28 mL, 3.51 mmol). After stirring at 0° C. for 1 h, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (5:1 to 2:1 hept-EA) gave the title compound as a pale yellow oil. TLC:rf (1:2 hept-EA)=0.50. LC-MS-conditions 01: tR=0.81 min; [M+H]+=219.89.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([NH2:30])=O)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[Si]([N:35]=[N+:36]=[N-:37])(C)(C)C>COCCOC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]3[NH:30][N:37]=[N:36][N:35]=3)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(N)=O)cc3)c(-c3ccc(F)cc3)sc2c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: COCCOC
Product: COc1ccc2c(Oc3ccc(/C=C/c4nnn[nH]4)cc3)c(-c3ccc(F)cc3)sc2c1
Temperature: 180 °C
Yield: 71.4 %

Procedure:
To a microwave vial, (E)-3-(4-((2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylamide (41 mg, 0.098 mmol) and Bu2SnO (2.433 mg, 9.77 mol) were suspended in DME (3 mL). The vial was charged with TMSN3 (0.013 mL, 0.098 mmol) and the reaction was heated for 60 min at 180° C. under microwave radiation. The reaction mixture was filtered to remove solids and concentrated onto silica gel. The crude material was purified by column chromatography (SiO2, 1-20% DCM/MeOH) to afford (E)-5-(4-((2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-1H-tetrazole (31 mg, 0.070 mmol, 71.4% yield) as an orange solid. 1H NMR (400 MHz, CD3OD) δ ppm=3.78 (s, 3H) 6.80-6.91 (m, 3H) 6.96-7.07 (m, 3H) 7.19 (d, J=8.59 Hz, 1H) 7.34 (d, J=2.53 Hz, 1H) 7.35-7.52 (m, 3H) 7.58-7.74 (m, 2H).
Reaction SMILES: [Cl:1]CCl.[OH-].[Na+].Cl.C[O:8][C:9]1[CH:10]=[C:11](/[C:15](=[CH:22]\[CH2:23][CH3:24])/[CH:16]([CH3:21])[CH2:17][N:18]([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=1>>[ClH:1].[CH3:20][N:18]([CH3:19])[CH2:17][CH:16](/[C:15](/[C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=1)=[CH:22]/[CH2:23][CH3:24])[CH3:21]
Reactant: CC/C=C(\c1cccc(OC)c1)C(C)CN(C)C
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC/C=C(\c1cccc(O)c1)C(C)CN(C)C
Yield: 86 %

Procedure:
The base was released with dichloromethane/sodium hydroxide solution from (15), which was prepared as in Example 13, and after drying the solution the dichloromethane was removed by distillation. Hydrochloride (18) was obtained, under the conditions given in Example 2, from the base thus obtained, in a yield of 86% theoretical and with a melting point of 120°-121° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][C:13](OC)=[O:14].[BH4-].[Li+]>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][CH2:13][OH:14]
Reactant: COC(=O)Cc1cc(OC)c(C#N)cc1Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(CCO)c(Cl)cc1C#N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl (2-chloro-4-cyano-5-methoxyphenyl)acetate (200 mg, 0.835 mmol) in THF (5 mL) was added 2M lithium borohydride (0.835 mL, 1.67 mmol) and the reaction was stirred at RT for 16 hours. The reaction was diluted with ether and quenched into water containing 2N HCl. The mixture was extracted twice with ethyl acetate and the organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The product mixture was separated by MPLC (40+S; 20-60% ethyl acetate/hexanes) to afford the title product. 1H-NMR (400 MHz, CDCl3) δ ppm 3.04 (t, J=6.4 Hz, 2H), 3.93 (t, J=6.4 Hz, 2H), 3.93 (s, 3H), 6.927 (s, 1H), 7.536 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:20](O)=[O:21]>C1(C)C=CC=CC=1>[CH:20]([NH:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:18][CH:17]=1)=[O:21]
Reactant: COc1ccc(CCc2ccc(N)cc2)cc1OC
Reactant: O=CO
Solvent: Cc1ccccc1
Product: COc1ccc(CCc2ccc(NC=O)cc2)cc1OC
Temperature: 25 °C
Yield: 99.1 %

Procedure:
The 4-[2-(3,4-dimethoxyphenyl)ethyl]benzenamine (9.9 g, 38.9 mmole) is dissolved in toluene (125 ml) containing formic acid (5.0 g, 108 mole) and refluxed for one hour. The reaction mixture is cooled to room temperature and evaporated to dryness. Recrystallization of the residue from toluene affords 11.0 g (82%) of N-formyl-4-[2-(3,4-dimethoxyphenyl)ethyl]benzenamine, mp 128°-130° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1)(=[O:36])[CH3:35]
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f19) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH2:16][C@H:17]([NH:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH2:30][C:31]([F:34])([F:33])[F:32])[CH3:18])=[CH:11][C:12]=2[C:14]#[N:15])[CH2:7][CH2:6]1.[OH-].[Na+].OO.S([O-])([O-])=[O:40].[Na+].[Na+]>CS(C)=O.O>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH2:16][C@H:17]([NH:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH2:30][C:31]([F:34])([F:32])[F:33])[CH3:18])=[CH:11][C:12]=2[C:14]([NH2:15])=[O:40])[CH2:7][CH2:6]1
Reactant: O=S([O-])[O-]
Reactant: C[C@H](Cc1cc(C#N)c2c(c1)CCN2CCCO)NCCOc1ccccc1OCC(F)(F)F
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H](Cc1cc2c(c(C(N)=O)c1)N(CCCO)CC2)NCCOc1ccccc1OCC(F)(F)F
Temperature: 22.5 °C
Reaction time: 5 h

Procedure:
1-(3-Hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carbonitrile(6.00 g) was dissolved in dimethylsulfoxide (75 mL), and to the solution was added 5 mol/L aqueous sodium hydroxide solution(4.50 mL). To the reaction mixture, 30% hydrogen peroxide (2.63 mL) was added little by little at not more than 25° C. The reaction mixture was stirred at 20 to 25° C. for 5 hours. To the reaction mixture, an aqueous sodium sulfite solution of sodium sulfite (2.1 g) dissolved in water (150 mL) was added carefully. The reaction mixture was extracted twice with ethyl acetate (50 mL). The combined ethyl acetate layer was extracted twice with 2 mol/L hydrochloric acid. The aqueous hydrochloric acid solution extracted was neutralized with sodium bicarbonate, and extracted twice with ethyl acetate (50 mL). The combined ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was cooled to give 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]-ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide (4.49 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][NH:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:21]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:30])[C@H:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)O>>[Si:1]([O:8][CH2:9][C@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][N:12]([CH:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(OCc1ccccc1)[C@@H](O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1ccccc1
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CN(C(C(=O)OCc2ccccc2)c2ccccc2)C[C@@H]1c1ccccc1

Procedure:
The title compound was prepared from 3-(R)-(t-butyldimethylsilyloxymethyl)-4-(S)-phenyl pyrrolidine (prepared above as Pyrrolidine 1) and (S)-mandelic acid, benzyl ester using a procedure analogous to that described in the preparation given above of Aldehyde 1. The title compound was obtained as a mixture of diastereomers: RF: 0.68 (4:1 v/v hexanes/EtOAc).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[Na].Cl[CH2:8][C:9]1([CH2:13]Cl)[CH2:12][O:11][CH2:10]1>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:8][C:9]1([CH2:13][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH2:12][O:11][CH2:10]1
Reactant: COCCO
Reactant: ClCC1(CCl)COC1
Agent: [Na]
Product: COCCOCC1(COCCOC)COC1
Temperature: 25 °C

Procedure:
To a 5 liter, three-neck flask, fitted with a reflux condenser, a stirrer and a thermometer, were added 1824 g (24 mole) of 2-methoxyethanol followed by 139 g (6 mole) of sodium metal. The flask temperature was then raised to mild reflux and thus maintained until all the sodium had dissolved. At this time, 465 g (3 mole) of 3,3-bis(chloromethyl)oxetane was added and heating was maintained for a further 24 hr. The mixture was then cooled to room temperature and the precipitated sodium chloride was removed by filtration. The filtrate was dissolved in an excess offwater, extracted with four portions of 500 ml methylene chloride, and then the combined organic layers were dried over magnesium sulfate. The solvent was then removed by evaporation and the required monomer isolated by fractional distillation, the fraction boiling at 85° C. and 0.1-mm pressure being collected. Redistillation from calcium hydride yielded 487 g of polymerizable grade monomer.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][O:9]2)=[CH:4][CH:3]=1.[CH3:11][NH2:12]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:9])[CH2:10][NH:12][CH3:11])=[CH:4][CH:3]=1
Reactant: Brc1ccc(C2CO2)cc1
Reactant: CN
Product: CNCC(O)c1ccc(Br)cc1

Procedure:
A solution of 2-(4-bromophenyl)-oxirane (0.5 g, 2.51 mmol) in methylamine (6.6 ml, 33% by volume in ethanol, 25.12 mmol) was stirred at room temperature under an atmosphere of nitrogen. After 18 hours the solvent was removed in vacuo and the residue was purified over flash silica eluting with dichloromethane: methanol:acetic acid:water (120:15:3:2) to afford the desired compound as the acetic acid salt. Further purification over a Phenomenex_Strata_SCX column eluting with methanol followed by 2N ammonia in methanol gave the desired product. LC/MS: (PS-B3) Rt 2.52 [M+H]+ 230.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](N2CCCC2)=[O:9])=[N:6][C:5]([Cl:15])=[CH:4][N:3]=1.[C:16]1([Mg]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O1CCCC1>O>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:6][C:5]([Cl:15])=[CH:4][N:3]=1
Reactant: Br[Mg]c1ccccc1
Reactant: Nc1ncc(Cl)nc1C(=O)N1CCCC1
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncc(Cl)nc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Amino-5-chloropyrazine-3-carboxylic acid pyrrolidide (9 g. or 0.04 mol) was added to a freshly prepared solution of 36.2 g. (0.2 mol) of phenylmagnesium bromide in 300 ml. of tetrahydrofuran cooled to 20°. After addition, the reaction mixture was stirred for 3 hours at room temperature and was then hydrolyzed by addition of 150 ml. of water. The organic layer was separated, dried over alumina, filtered and evaporated. Crystallization of the oil obtained from ether yielded 2 g. (50%) of the above-named product as yellow crystals, m.p. 158°-161°. The analytical sample was recrystallized from ethyl acetate, m.p. 160°-161°.
Reaction SMILES: [F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[N:12]=[C:11](S(C)=O)[C:10]2[C:5](=[CH:6][C:7]([C:16]#[N:17])=[CH:8][CH:9]=2)[N:4]=1.BrC1C=C2C(C(SC)=[N:32][C:33]([C:37](F)(F)[C:38]3[CH:43]=CC(F)=C[N:39]=3)=[N:34]2)=CC=1>>[F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[N:12]=[C:11]([NH:32][C:33]2[CH:37]=[C:38]([CH3:43])[NH:39][N:34]=2)[C:10]2[C:5](=[CH:6][C:7]([C:16]#[N:17])=[CH:8][CH:9]=2)[N:4]=1
Reactant: CS(=O)c1nc(C(F)(F)c2ccc(F)cn2)nc2cc(C#N)ccc12
Reactant: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2cc(Br)ccc12
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3cc(C#N)ccc23)n[nH]1

Procedure:
2-(Difluoro(5-fluoropyridin-2-yl)methyl)-4-(5-methyl-1H-pyrazol-3-ylamino)quinazoline-7-carbonitrile was prepared as a white solid (12 mg, 10%) by following a procedure analogous to that described in Example 7 Step D, substituting 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylsulfinyl)quinazoline-7-carbonitrile for the 7-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline used in Example 7. 1H NMR (300 MHz, DMSO-d6) δ 12.23-12.30 (m, 1H), 11.06 (s, 1H), 8.86 (d, J=8.7 Hz, 1H), 8.67 (s, 1H), 8.42 (d, J=1.1 Hz, 1H), 7.97-8.05 (m, 3H), 5.99 (s, 1H), 2.18 (s, 3H); LC-MS (ESI) m/z 396 (M+H)+.