Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([P:3](=[O:17])([CH:15]=[CH2:16])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH3:14])[CH:5]=1)=[CH2:2].Cl.[CH2:19]([NH2:21])[CH3:20].[OH-].[Na+].C(N)C1C=CC=CC=1>C1COCC1>[CH2:19]([N:21]1[CH2:16][CH2:15][P:3](=[O:17])([C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH3:14])[CH:5]=2)[CH2:1][CH2:2]1)[CH3:20]
Reactant: C=CP(=O)(C=C)c1ccc([N+](=O)[O-])c(OC)c1
Reactant: CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: NCc1ccccc1
Solvent: C1CCOC1
Product: CCN1CCP(=O)(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Temperature: 105 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
Diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide (0.480 g, 1.94 mmol), ethylamine hydrochloride (0.174 g, 2.12 mmol), and 1 N NaOH (2 mL) were dissolved in 50% aqueous THF (5 mL) and heated to 105° C. under nitrogen. After one hour, another portion of benzylamine was added to the reaction mixture. The reaction mixture was refluxed for an additional 2 h, and then cooled to rt. The reaction mixture was partitioned between saturated aqueous NaHCO3 and CH2Cl2. The aqueous phase was washed once with CH2Cl2 and the organic layers were combined. The organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-10% 7N ammonia in methanol:dichloromethane) to afford the compound (0.267 g, 46% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:34]=[N:33][N:32]([CH:35]([CH3:37])[CH3:36])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH2:24][CH:25]=2)[CH:19]=1)=[O:13].[CH:38]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH2:39]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:34]=[N:33][N:32]([CH:35]([CH3:37])[CH3:36])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([CH:26]3[CH2:27][CH2:28][N:29]([CH2:39][CH2:38][S:40]([CH3:43])(=[O:42])=[O:41])[CH2:30][CH2:31]3)[CH2:24][CH:25]=2)[CH:19]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C4CCNCC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: C=CS(C)(=O)=O
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C4CCN(CCS(C)(=O)=O)CC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 41 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1-(piperidin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.2 g, 0.397 mmol) in MeOH (2 mL), methyl vinyl sulfone (0.063 g, 0.596 mmol) was added and stirred it at room temperature for 12 h. After completion of reaction, solvent was removed under reduced pressure and water was added to it. Extraction was carried out using 10% MeOH/DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure, finally the residue was washed with diethyl ether to provide the desired compound (41% yield). LCMS: 610.45 (M+1)+; HPLC: 97.26% (@ 254 nm) (Rt; 6.037); 1H NMR (DMSO-d6, 400 MHz) δ 11.54 (s, 1H), 8.82 (t, 1H), 8.27 (s, 1H), 7.80 (s, 1H), 6.88 (s, 1H), 5.89 (s, 1H), 5.21-5.17 (m, 1H), 4.37 (d, 2H, J=4.4 Hz), 3.32-3.25 (m, 4H), 3.02 (s, 3H), 2.95 (d, 2H, J=10.40 Hz), 2.73 (d, 2H, J=4 Hz), 2.67 (bs, 4H), 2.32 (m, 2H), 2.20 (s, 3H), 2.12 (s, 3H), 1.99-1.94 (m, 2H), 1.81-1.79 (m, 2H), 1.49 (d, 6H, J=6.4 Hz), 1.45 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([C@H:18]([CH3:22])[CH2:19][CH:20]=[O:21])=[C:8]2[CH3:23])=[CH:4][CH:3]=1.[OH-:26].[Na+].O>C(O)C.[N+]([O-])([O-])=O.[Ag+]>[Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([C@H:18]([CH3:22])[CH2:19][C:20]([OH:26])=[O:21])=[C:8]2[CH3:23])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: COc1ccc2c(c1)c([C@H](C)CC=O)c(C)n2Cc1ccc(Br)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)c([C@H](C)CC(=O)O)c(C)n2Cc1ccc(Br)cc1
Yield: 97 %

Procedure:
A solution of (R)-3-[1-(4-Bromo-benzyl)-5-methoxy-2-methyl-1H-indol-3-yl]-butanal (110 mg, 0.250 mmol) and silver nitrate (59.7 mg, 0.275 mmol) in 1.3 ml absolute ethanol was treated with a solution of 5N NaOH in ethanol (1:5, 0.9 ml, 0.75 mmol NaOH). After 45 min this was treated with 10 ml water, acidified to pH 3 and extracted with CHCl3 (5×20 ml) rinsing each extract with brine. The combined organics were dried over Na2SO4 and concentrated in vacuo to provide, after silica gel chromatography the title compound as a pale yellow solid (101 mg, 97% yield). IR (film) 3425, 2961, 2934, 2833, 1706, 1483, 1451, 1405, 1228, 1156, 1010, 796, 755 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.36 (d, J=9.0 Hz, 2H, ArH), 7.11 (d, J=2.4 Hz, 1H, ArH), 7.04 (d, J=8.7, 1H, ArH), 6.77-6.73 (m, 3H, ArH), 5.18 (s, 2H NCH2), 3.86 (s, 3H, OCH3) 3.56 (dt, J=7.2, 21.9 Hz, 1H ArCH), 2.86 (d, J=3.6 Hz, 1H, CH2CO); 2.83 (d, J=3.3 Hz, 1H, CH2CO); 2.27 (s, 3H, ArCH3) 1.49 (d, J=7.2 Hz, 3H, CHCH3); 13C NMR (75 MHz, CDCl3) δ 178.0, 153.7, 137.3, 133.8, 133.0, 132.0, 127.7, 126.7, 121.2, 118.8, 114.6, 110.1, 109.9, 102.4, 56.3, 46.3, 41.5, 28.6, 21.1, 10.9; HRMS (CI) exact mass calcd for (C21H23BrNO3) (M+1) requires m/z 416.0861, found m/z 416.0867. [α]D=−30.9 (c=1.0, CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)=[C:12]([C:14]#[N:15])[N:13]=1.CO>[Pd].CCOC(C)=O>[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:11]2[O:10][C:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[N:13][C:12]=2[C:14]#[N:15])=[CH:22][CH:21]=1
Reactant: N#Cc1nc(-c2c(F)cccc2F)oc1Nc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: N#Cc1nc(-c2c(F)cccc2F)oc1Nc1ccc(N)cc1
Yield: 90.7 %

Procedure:
A solution of 2-(2,6-difluorophenyl)-5-(4-nitrophenylamino)oxazole-4-carbonitrile (0.435 g, 1.271 mmol) in 50:50 MeOH:EtOAc (10 ml) was hydrogenated using a 10% Pd/C catalyst at 30° C. at atmospheric pressure using the Thales H-Cube at a flow rate of 1 ml/min. The organic layer was then reduced in vacuo to yield 5-(4-aminophenylamino)-2-(2,6-difluorophenyl)oxazole-4-carbonitrile (0.360 g, 1.153 mmol, 90%). 1H NMR (CD3OD) δ 6.74 (2H, d), 7.10 (2H, d), 7.14 (2H, t), 7.55 (1H, m). LCMS (2) Rt: 2.47 min; m/z (ES+) 313.
Reaction SMILES: C([SiH](CC)CC)C.[CH3:8][O:9][C:10](=[O:30])[CH2:11][CH2:12][C:13]1[C:14](=[O:29])[N:15](CC2C=CC(OC)=CC=2OC)[CH2:16][CH:17]=1>FC(F)(F)C(O)=O>[CH3:8][O:9][C:10](=[O:30])[CH2:11][CH2:12][C:13]1[C:14](=[O:29])[NH:15][CH2:16][CH:17]=1
Reactant: COC(=O)CCC1=CCN(Cc2ccc(OC)cc2OC)C1=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCC1=CCNC1=O
Yield: 46.9 %

Procedure:
0.1 ml of triethylsilane (0.63 mmol) was added to the reaction solution containing 200 mg of 3-[1-(2,4-dimethoxybenzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic acid methyl ester (0.63 mmol) dissolved in 0.7 ml of trifluoroacetic acid solution at 0° C. After the reaction mixture was heated for 1 hr, the mixture was filtered and concentrated in vacuo to remove solvent. Then the resulting mixture was dissolved in 20 ml of chloroform solution to separate into an organic layer and water layer. The organic layer was washed with 5 ml of saturated NaHCO3 solution and 5 ml of saturated NaCl solution, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resultant was purified by Silica gel column chromatography with a solvent mixture mixed with EtOAc and hexanes (19:1) as an eluant to give 50 mg of 3-(2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-propionic acid methyl ester (2f) (yield: 47%).
Reaction SMILES: [CH2:1]([C:3]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].[CH3:16][NH:17][C@H:18]1[CH2:37][N:22]2[C:23]3[C:28]([C:29]([CH2:30][C:31]([O:33]CCC)=[O:32])=[C:21]2[CH2:20][CH2:19]1)=[CH:27][CH:26]=[CH:25][CH:24]=3>>[CH2:1]([C:3]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([CH2:7][CH3:8])[C:4]([N:17]([CH3:16])[C@H:18]1[CH2:37][N:22]2[C:23]3[C:28]([C:29]([CH2:30][C:31]([OH:33])=[O:32])=[C:21]2[CH2:20][CH2:19]1)=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:5])[CH3:2]
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: CCC(CC)(C(=O)Cl)c1ccc(F)cc1
Product: CCC(CC)(C(=O)N(C)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1)c1ccc(F)cc1

Procedure:
The title compound was prepared using analogous procedures described in Example 2 (Method B) from 2-ethyl-2-(4-fluorophenyl)butanoyl chloride and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido [1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 451.
Reaction SMILES: [P:1](=[O:9])([N:6]=[C:7]=[O:8])([S:4][CH3:5])[O:2][CH3:3].[NH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>CCOCC>[CH3:3][O:2][P:1]([NH:6][C:7]([NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:8])([S:4][CH3:5])=[O:9]
Reactant: CCOC(=O)CN
Reactant: COP(=O)(N=C=O)SC
Solvent: CCOCC
Product: CCOC(=O)CNC(=O)NP(=O)(OC)SC
Yield: 80.7 %

Procedure:
To a solution of 6.1 grams (g) of O,S-dimethyl phosphoroisocyanatidothioate in 100 milliliters (ml) of ether was added dropwise with stirring 3.5 g of ethyl glycinate. A solid soon began to precipitate and after about 1 hour this was collected by filtration. The solid was recrystallized from ethanol to obtain 7.4 g of the title compound (77 percent of theory) as white crystals melting at 143°-145° C.
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[S:11]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:13])=[O:12].[H-].[Na+].Br[CH2:26][C:27]([O:29][CH3:30])=[O:28].C(=O)(O)[O-].[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.CN(C=O)C.CC(C)=O.O>[CH3:30][O:29][C:27](=[O:28])[CH2:26][N:14]([S:11]([C:7]1[S:8][CH:9]=[CH:10][C:6]=1[CH:2]=[O:3])(=[O:12])=[O:13])[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1
Reactant: COc1ccc(NS(=O)(=O)c2sccc2C2OCCO2)cc1
Reactant: COC(=O)CBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CN(c1ccc(OC)cc1)S(=O)(=O)c1sccc1C=O
Reaction time: 0.5 h
Yield: 33.2 %

Procedure:
To a solution of the product of Step A (10.21 g, 29.9 mmol) in anhydrous THF (100 mL) and DMF (15 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 1.32 g, 32.9 mmol). After stirring for 30 min, methyl 2-bromoacetate (5.49 g, 35.9 mmol) was added and stirring continued at ambient temperature for 4 h. The reaction mixture was poured into a saturated solution of sodium bicarbonate (150 mL) and extracted with ethyl acetate (2×100 mL). The combined extracts was dried (MgSO4) and evaporated to give an oil which was dissolved in acetone (150 mL) and p-toluenesulfonic acid (2.5 g) was added. This solution was stirred at ambient temperature for 2 h, heated at reflux temperature for 5 h, cooled and mixed with water (100 mL) and sodium carbonate (1.0 g). Acetone was evaporated and the aqueous was extracted with ethyl acetate (2×100 mL). The combined extracts were dried (MgSO4) and evaporated to a residue which was purified by column chromatography (silica, 40% ethyl acetate/hexane) to give an oil (3.67 g, 33%).
Reaction SMILES: I[C:2]1[C:3]2[C:4](=[CH:8][N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:10]=2)[N:5]=[CH:6][CH:7]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[F:62][C:63]1[C:64]([C:70]2[CH:75]=[C:74]([NH2:76])[CH:73]=[CH:72][N:71]=2)=[N:65][C:66]([CH3:69])=[CH:67][CH:68]=1.CC([O-])(C)C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:62][C:63]1[C:64]([C:70]2[CH:75]=[C:74]([NH:76][C:2]3[C:3]4[C:4](=[CH:8][N:9]([CH2:11][C:12]5[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=5)[N:10]=4)[N:5]=[CH:6][CH:7]=3)[CH:73]=[CH:72][N:71]=2)=[N:65][C:66]([CH3:69])=[CH:67][CH:68]=1
Reactant: COc1ccc(Cn2cc3nccc(I)c3n2)cc1
Reactant: Cc1ccc(F)c(-c2cc(N)ccn2)n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1ccc(Cn2cc3nccc(Nc4ccnc(-c5nc(C)ccc5F)c4)c3n2)cc1
Temperature: 120 °C
Yield: 50.4 %

Procedure:
7-Iodo-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridine (198 mg, 0.541 mmol), Tris(dibenzylideneacetone)dipalladium(0) (12.39 mg, 0.014 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (78 mg, 0.135 mmol), 3′-fluoro-6′-methyl-2,2′-bipyridin-4-amine (110 mg, 0.541 mmol) and sodium 2-methylpropan-2-olate (156 mg, 1.624 mmol) were combined in dioxane (5 mL). The mixture was heated at 120° C. for 2 hours then cooled and purified by preparative HPLC using a Sunfire Prep 5 μm C18, 75×30 mm column eluting with a gradient of 10-50% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA) to afford N-(3′-fluoro-6′-methyl-2,2′-bipyridin-4-yl)-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridin-7-amine (120 mg, 50.3% yield) as a yellow solid. MS [M+H] found 441.4.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:21][C:22]([CH:24]1[CH2:26][CH2:25]1)=[O:23]>CN(C)C=O>[CH:24]1([C:22](=[O:23])[CH2:21][NH:1][C:2]2[C:3]([CH3:11])=[CH:4][C:5]([F:10])=[C:6]([CH:9]=2)[C:7]#[N:8])[CH2:26][CH2:25]1
Reactant: Cc1cc(F)c(C#N)cc1N
Reactant: O=C(CBr)C1CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(F)c(C#N)cc1NCC(=O)C1CC1
Temperature: 60 °C
Yield: 76.5 %

Procedure:
5-Amino-2-fluoro-4-methylbenzonitrile (12 g, 80 mmol) was dissolved in anhydrous N,N-dimethylformamide (160 mL) under nitrogen, and potassium carbonate (13.27 g, 96 mmol) and potassium iodide (14.61 g, 88 mmol) were added as solids with stirring. The reaction was stirred for 5 minutes at room temperature and then bromomethyl cyclopropylketone (20.24 mL, 180 mmol) was added. The reaction mixture was heated to 60° C. for 3 hours, and then the solvents removed under reduced pressure. The residue was dissolved in EA (400 mL) and washed with 400 mL of water. The organic layer was dried over magnesium sulfate, and solvent was removed under reduced pressure. The residue was re-dissolved in a minimum amount of EA, and hexanes were added to bring the solution to 3:1 hexanes: EA by volume. The product precipitated out of solution and was collected by filtration to provide 5-(2-cyclopropyl-2-oxoethylamino)-2-fluoro-4-methylbenzonitrile (14.19 g, 61.2 mmol). LC/MS (m/z: 233, M+1)
Reaction SMILES: [CH:1]1([NH:8][C:9]([CH2:11][C:12]2[CH:24]=[CH:23][C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15][C:14]=3[CH:13]=2)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.Cl.[OH-].[Na+]>O1CCCC1.C(Cl)(Cl)Cl>[CH:1]1([NH:8][CH2:9][CH2:11][C:12]2[C:13]3[CH2:14][C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:21]=3[CH:22]=[CH:23][CH:24]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(Cc1ccc2c(c1)Cc1ccccc1-2)NC1CCCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CO
Product: c1ccc2c(c1)Cc1c(CCNC3CCCCCC3)cccc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
In dry tetrahydrofuran (30 ml) was dissolved 2-cycloheptylcarbamoylmethylfluorene (1.9 g) followed by dropwise addition of borane-methyl sulfide complex (1.8 ml) with ice-cooling. The mixture was then refluxed for 4 hrs, at the end of which time methanol (0.72 ml) was added with ice-cooling. The mixture was stirred at room temperature for 30 minutes, followed by addition of concentrated hydrochloric acid (1.8 ml) with ice-cooling. The mixture was refluxed again for 30 minutes. The reaction mixture was then cooled with ice and the resulting solid was recovered by filtration and washed with ether. The solid matter thus obtained was dissolved in chloroform and the solution was alkalinized with aqueous sodium hydroxide solution. The chloroform layer was taken and dried and the solvent was distilled off under reduced pressure to give 2-cycloheptylaminoethylfluorene (1.2 g).
Reaction SMILES: [CH2:1]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:6]([C@H:7]2[CH2:8][CH2:9][C@H:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:11][CH2:12]2)[CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)CN[C@H]1CC[C@H](c2ccccc2)CC1
Product: CC(C)(C)CN(C(=O)c1ccc(Cl)cc1)[C@H]1CC[C@H](c2ccccc2)CC1

Procedure:
from trans-N-neopentyl-4-phenylcyclohexylamine and 4-chlorobenzoylchloride Colourless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH:8]=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:10]([O:17][C:18]([NH:20][CH:21](P(OC)(OC)=O)[C:22]([O:24][CH3:25])=[O:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CN(C)C(N(C)C)=N>O1CCCC1>[CH2:10]([O:17][C:18]([NH:20]/[C:21](=[CH:1]\[C:2]1([CH3:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)/[C:22]([O:24][CH3:25])=[O:23])=[O:19])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: CC1(C=O)CCCCC1
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/C1(C)CCCCC1)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 96 h

Procedure:
1-Methylcyclohexanecarbaldehyde (2.66 g, 21.08 mmol) and methyl {[(benzyloxy)carbonyl]amino}(dimethoxyphosphoryl)acetate (6.63 g, 20.02 mmol, 0.95 equivalent) are dissolved in 75 ml of tetrahydrofuran and cooled to −78° C. At −78° C., N,N,N′,N′-tetramethylguanidine (27.92 g, 0.24 mol, 11.5 equivalents) is added dropwise and then stirred at −78° C. for 15 min and subsequently at room temperature for 4 days. The mixture is then extracted by shaking with ethyl acetate (twice 100 ml) and water, and the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulphate. After concentration, the crude product is chromatographed (Biotage 40M, cyclohexane/ethyl acetate 6/1, 27.5 ml/min). 0.91 g (13% of theory) of the title compound is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[OH:15])[CH:5]=[CH:4][N:3]=1.[NH2:16][C:17](=[O:31])[C@@H:18]([NH:20][C:21]1[N:26]=[C:25](Cl)[N:24]=[C:23]([C:28]([NH2:30])=[O:29])[CH:22]=1)[CH3:19].C([O-])([O-])=O.[Cs+].[Cs+].ClCCl>CN(C=O)C.[Cu]I.C(Cl)Cl.CO>[NH2:16][C:17](=[O:31])[C@@H:18]([NH:20][C:21]1[N:26]=[C:25]([O:15][C:9]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=2)[N:24]=[C:23]([C:28]([NH2:30])=[O:29])[CH:22]=1)[CH3:19]
Reactant: Nc1cc(-c2cc(Cl)ccc2O)ccn1
Reactant: C[C@H](Nc1cc(C(N)=O)nc(Cl)n1)C(N)=O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: C[C@H](Nc1cc(C(N)=O)nc(Oc2ccc(Cl)cc2-c2ccnc(N)c2)n1)C(N)=O
Temperature: 120 °C
Reaction time: 4 h
Yield: 88.3 %

Procedure:
A mixture of 2-(2-aminopyridin-4-yl)-4-chlorophenol (110 mg, 0.5 mmol), (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-chloropyrimidine-4-carboxamide (122 mg, 0.5 mmol), CuI (10 mg, 0.05 mmol) and Cs2CO3 (191 mg, 0.5 mmol) in DMF (3 mL) was stirred at 120° C. for 4 hrs. The reaction mixture was cooled to room temperature, worked up with dichloromethane and subjected to flash chromatography (DCM/methanol) to give (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(2-(2-aminopyridin-4-yl)-4-chlorophenoxy)pyrimidine-4-carboxamide as a white solid (189 mg, yield 85%). 1H NMR (CD3OD): 7.82-8.05 (1H, br), 7.6 (2H, m), 7.40 (2H, m), 6.80 (1H, m), 6.60 (2H, m), 4.23-4.10 (1H, m), 1.35 (3′-1, d, J=7.0 Hz). LC/MS: m/z=428 [M+H]+.
Reaction SMILES: C1COCC1.[C:6]([O:10][C:11]([N:13]1[C@H:17]([CH2:18][F:19])[C@@H:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[O:30][N:29]=[C:28]([C:31](OCC)=[O:32])[CH:27]=3)=[CH:22][CH:21]=2)[O:15][C:14]1([CH3:37])[CH3:36])=[O:12])([CH3:9])([CH3:8])[CH3:7].[BH4-].[Na+]>CO>[F:19][CH2:18][C@@H:17]1[C@@H:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[O:30][N:29]=[C:28]([CH2:31][OH:32])[CH:27]=3)=[CH:22][CH:21]=2)[O:15][C:14]([CH3:37])([CH3:36])[N:13]1[C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12]
Reactant: CCOC(=O)c1cc(-c2ccc([C@H]3OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]3CF)cc2)on1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(CO)no3)cc2)OC1(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
To a cooled (0° C.) THF (25 ml) solution of ethyl 5-(4-((4S,5R)-3-(tert-butoxycarbonyl)-4-(fluoromethyl)-2,2-dimethyloxazolidin-5-yl)phenyl)isoxazole-3-carboxylate (1.0 g, 2.2 mmol) is added sodium borohydride (0.25 g, 6.7 mmol) followed by methanol (3 ml added slowly). The reaction is stirred for 30 minutes at 0° C. and for one hour at room temperature. The excess sodium borohydride is quenched by the addition of saturated aqueous ammonium chloride (5 ml). The reaction mixture is diluted with ethyl acetate (50 ml) and water (25 ml). The layers were mixed and allowed to separate. The organic phase is collected, dried over sodium sulfate and concentrated to give the product, (4S,5R)-tert-butyl 4-(fluoromethyl)-5-(4-(3-(hydroxymethyl)isoxazol-5-yl)phenyl)-2,2-dimethyl-oxazolidine-3-carboxylate (875 mg, 96%), as a viscous oil. 1H NMR (400 MHz, CDCl3) 1.52 (s, 9H) 1.59 (s, 3H) 1.74 (br. s., 3H) 2.03-2.08 (m, 1H) 3.83-3.96 (m, 1H) 4.40-4.60 (m, 2H) 4.85 (d, J=6.06 Hz, 2H) 5.19 (d, J=7.58 Hz, 1H) 6.63 (s, 1H) 7.57 (d, J=8.34 Hz, 2H) 7.82 (d, J=8.34 Hz, 2H); m/z (CI) 407 ([M+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH2:11][CH2:10][O:9][C:8]1=[O:12])(=O)C>CO>[O:4]1[CH2:1][CH2:11][CH:7]([C:8]([O:9][CH3:10])=[O:12])[CH2:6][CH2:5]1
Reactant: CC(=O)OCCC1CCOC1=O
Solvent: CO
Product: COC(=O)C1CCOCC1

Procedure:
A solution consisting of 57 wt % of 3-(2'-acetoxyethyl)-dihydro-2(3H)furanone and 43wt % of methanol was pumped into an evaporator (300° C.) at a rate of 170 g per hour, whence the vapors were passed together with 80 L/h of nitrogen over 560 g (950 mL) of Al2O3 (1.3 mm extrudates) at a reactor temperature of 250° C. using a trickle-bed method. The gaseous effluent was condensed in cold traps and analyzed by gas chromatography. 61 mol % of methyl tetrahydropyran-4-carboxylate was formed, plus 26 mol % of 3-(2'-methoxyethyl)-dihydro-2(3H)furanone and 5 mol % of 5-oxaspiro[2.4]heptan-4-one. The conversion of 3-(2'-acetoxyethyl)-dihydro-2(3H)furanone was 97%.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH3:6])=[O:4].Cl.[CH3:8][O:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].C(=O)([O-])O.[Na+]>>[CH3:8][O:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([NH:16][CH2:2][C:3]([O:5][CH3:6])=[O:4])[CH:17]=[CH:18][CH:19]=1
Reactant: COCCOc1cccc(N)c1
Reactant: COC(=O)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COCCOc1cccc(NCC(=O)OC)c1
Yield: 98.3 %

Procedure:
Methyl chloroacetate (6.2 ml, 70.3 mmol), the free base of Intermediate 51 (7.84 g, 46.9 mmol) and sodium hydrogencarbonate (7.9 g 93.8 mmol) were heated at 100° C. for 24 h. The reaction was cooled, extracted with ethyl acetate, washed with water, 2N hydrochloric acid and brine, dried (K2CO3) and evaporated to give the title compound (Intermediate 52; 11.03 g, 98%) as a brown oil.