Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([O:14]CC)=[O:13])[C:6]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21][C:5]=3[C:4]=2[C:3]=1[Cl:29].[OH-].[K+].Cl>C1COCC1.O>[C:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][C:5]2[C:4]3[C:3]([Cl:29])=[C:2]([Cl:1])[CH:10]=[CH:9][C:8]=3[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[CH2:17][CH2:18]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)Cn1c2c(c3c(Cl)c(Cl)ccc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3ccc(Cl)c(Cl)c23)CC1
Temperature: 60 °C

Procedure:
To a solution of tert-butyl 9,10-dichloro-6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (1.5 g, 3.4 mmol) in THF (15 mL), a solution of KOH (25 mg, 4.4 mmol) dissolved in H2O (10 mL) was added and heated to 60° C. The reaction was cooled to rt after 2 h. The reaction was made acidic with 10% aqueous HCl and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and the crude acid was concentrated: 1H NMR (300 MHz, DMSO) δ 13.11 (br s, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.23 (d, J=8.7 Hz, 1H), 5.04 (s, 2H), 3.62 (m, 4H), 2.93 (m, 2H), 1.41 (s, 9H); HRMS (FAB) calcd for C19H22Cl2N2O4+H 413.1035, found 413.1050.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].C([Si](C)(C)[O:20][CH2:21][CH2:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=1[Cl:32])(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S([O-])(O)=O.[Na+]>O.CC(N(C)C)=O>[Cl:32][C:25]1[CH:26]=[C:27]([C:28]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:30]=[CH:31][C:24]=1[O:23][CH2:22][CH2:21][OH:20]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(C=O)cc1Cl
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OCCO)c(Cl)c3)nc2c1
Temperature: 150 °C
Reaction time: 17 h
Yield: 14.1 %

Procedure:
A mixture of 3-chloro-4-hydroxy-benzaldehyde (227 mg, 1.45 mmol), (2-bromoethoxy)-tert-butyldimethylsilane (347 mg, 1.45 mmol), cesium carbonate (709 mg, 2.18 mmol) and DMSO (2 mL) was stirred at 80° C. for 17 h. The reaction mixture was cooled to room temperature and water (50 mL) was added. The resulting precipitate was filtered off, washed with water, air-dried, dissolved in a small amount of ethyl acetate and purified by column chromatography. 4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-3-chlorobenzaldehyde was obtained as a white solid (yield: 267 mg, 58%). To a 100 mL round-bottomed flask was added 2-amino-4,6-dimethoxy-benzamide (166 mg, 0.85 mmol), 4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-3-chlorobenzaldehyde (267 mg, 0.85 mmol), p-toluenesulfonic acid monohydrate (21 mg, 0.11 mmol), sodium hydrogensulfite (216 mg, 1.2 mmol) and dimethylacetamide (5 mL). The mixture was stirred in a 150° C. oil bath under nitrogen for 17 h. After cooling to room temperature, water (50 mL) was added. The precipitate was filtered off, washed with water and air-dried. The crude product was purified by column chromatography to give 2-(3-chloro-4-(2-hydroxyethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (45 mg, 23%). Selected data: MS (ES) m/z: 377.03; MP 287-288° C. (decomposed).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH:7]2[CH2:11][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9](=[O:19])[CH2:8]2)C(=O)C2=CC=CC=C12.O.NN.C(O)(=O)/C=C/C(O)=O>C(O)C>[CH2:12]([N:10]1[CH2:11][CH:7]([CH2:6][NH2:5])[CH2:8][C:9]1=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1CC(CN2C(=O)c3ccccc3C2=O)CN1Cc1ccccc1
Agent: NN
Agent: O=C(O)/C=C/C(=O)O
Solvent: O
Solvent: CCO
Product: NCC1CC(=O)N(Cc2ccccc2)C1

Procedure:
54 g (0.16 mol) of 4-phthalimidomethyl-1-benzyl-pyrrolidin-2-one are stirred into 1.3 l of ethyl alcohol after the addition of 32 g of hydrazine hydrate for 4 hours at room temperature. The precipitate (phthalic acid hydrazide) is removed by suction filtering the filtrate is evaporated down. 500 ml of methylene choloride are added to the residue which is then extracted three times with 100 ml of water. The organic phase is dried and evaporated down. The residue remaining is dissolved in 500 ml of methanol and 20 g (0.17 mol) of solid fumaric acid are added in batches thereto, with stirring, at boiling temperature. As the mixture cools, colorless crystals are precipitated, which are then suction filtered and washed with methanol and ether.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)#[N:2].C(N(CC)CC)C.[F:22][C:23]([F:38])([F:37])[C:24]1[CH:25]=[C:26]([N:34]=[C:35]=[O:36])[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1>ClCCl.O>[F:22][C:23]([F:37])([F:38])[C:24]1[CH:25]=[C:26]([NH:34][C:35]([N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])[CH2:10][CH2:11]2)=[O:36])[CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=1
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccccc1N1CCN(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2-Cyanophenyl)piperazine (1.0 g, 5.34 mmol) was dissolved in 25 mL of dichloromethane. Then, triethylamine (820 μL, 5.88 mmol) was added, followed by 3,5-bis(trifluoromethyl)phenyl isocyanate (1020 μL, 5.87 mmol). The reaction stirred at room temperature overnight. The reaction mixture was diluted with 50 mL of water and extracted three times with 25 mL portions of ethyl acetate. The combined organic fractions were washed twice with 25 mL of 0.1 M HCl, once with 25 mL of water, and once with 25 mL of saturated sodium bicarbonate. The organic fraction was dried with magnesium sulfate and concentrated under vacuum. The crude product was used without further purification.
Reaction SMILES: CON(C)[C:4](=[O:16])[C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:7])[CH3:6].[CH3:18][Li].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O.O>[CH3:7][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])([C:4](=[O:16])[CH3:18])[CH3:6]
Reactant: [Li]C
Reactant: CON(C)C(=O)C(C)(C)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)C(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.8 %

Procedure:
To a solution of tert-butyl 1-(methoxy(methyl)amino)-2-methyl-1-oxopropan-2-ylcarbamate (4.26 g, 17.30 mmol) in THF (100 mL) at −70° C. was added drop wise methyl lithium (32.4 mL, 51.9 mmol). Cold bath was replaced with −40° C. bath and the reaction was stirred for 4 hours. Saturated NH4Cl solution (10 mL) was then added cautiously to quench the reaction. The reaction mixture was then allowed to warm to room temperature, and diluted with EtOAc (100 mL) and water (50 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organics were then dried (Na2SO4) and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography (10-50% EtOAc-Hexanes) to afford the desired product as a white solid (2.36 g). LCMS m/z 224.2 (M+Na)+, Rt 0.7 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7].[C:14]12(O)[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.S(=O)(=O)(O)O>ClCCl>[C:14]12([C:11]3[CH:10]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:12]=3[OH:13])[C:6]([O:8][CH3:9])=[O:7])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COC(=O)c1cc(OC)c(O)c(C23CC4CC(CC(C4)C2)C3)c1

Procedure:
12.37 g (68 mM) of methyl 3-methoxy-4-hydroxybenzoate in 150 ml of dichloromethane are treated with 10.33 g (68 mM) of adamantanol and 3.72 ml of concentrated sulphuric acid under the conditions described in Example 9(a). After the same treatment, there are isolated 20.3 g (94.5%) of the expected derivative, of melting point 179° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19].C([O-])(=O)C.[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:18][OH:19])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccccn1)c1ccc(F)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: ON=C(Cc1ccccn1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.3 %

Procedure:
To a solution of 1-(4-fluorophenyl)-2-pyridin-2-ylethanone (6.27 g 29 mmol) in methanol (100 ml) was added a solution of hydroxylamine hydrochloride (9.6 g 130 mmol) and sodium acetate (15.6 g) in water (80 ml) and the reaction was stirred at room temperature for 24 hours. The resulting precipitate was filtered off and dried to give the title compound as a white solid (5.83 g 87%). (M-H2O)H+: 213; NMR: (CDCl3): δ 4.42 (2H, s) 7.00 (2H, t) 7.14 (1H, m) 7.28 (1H, d) 7.59 (1H, dt) 7.72 (2H, m) 8.55 (1H, m) 8.96 (1H, br).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C@H:7]1[CH2:30][O:29][C:10]2=[CH:11][CH:12]=[C:13]3[C:17]([N:16]([CH2:18][C@H:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH3:20])[N:15]=[CH:14]3)=[C:9]2[CH2:8]1)=[N+]=[N-].C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39].C(=O)(O)[O-].[Na+]>CO.[Pd]>[C:25]([Si:22]([CH3:24])([CH3:23])[O:21][C@H:19]([CH3:20])[CH2:18][N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]3[O:29][CH2:30][C@H:7]([O:6][CH2:5][CH2:4][NH:1][C:38](=[O:40])[CH3:39])[CH2:8][C:9]3=2)[CH:14]=[N:15]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: C[C@H](Cn1ncc2ccc3c(c21)C[C@@H](OCCN=[N+]=[N-])CO3)O[Si](C)(C)C(C)(C)C
Reactant: CC(=O)Cl
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)NCCO[C@H]1COc2ccc3cnn(C[C@@H](C)O[Si](C)(C)C(C)(C)C)c3c2C1
Reaction time: 8 h
Yield: 54.2 %

Procedure:
A mixture of the product from step B (0.73 g, 1.69 mmol) and palladium-on-carbon (10%, 0.07 g) in methanol (50 mL) was placed under an atmosphere of hydrogen and stirred overnight. The mixture was filtered, evaporated to an oil (0.61 g, 88%) which was dissolved in dichloromethane (30 mL). To this solution was added triethylamine (0.304 g, 3.01 mmol) and acetyl chloride (0.142 g, 0.129 mL, 1.81 mmol), and the mixture was stirred for 1 h, mixed with a saturated solution of sodium bicarbonate (100 mL) and extracted with ethyl acetate. The dried extracts were evaporated to a residue which was purified by chromatography (silica, gradient, 30% to 90% ethyl acetate in hexane) to give an oil (0.41 g, 61%): LCMS (+ESI) m/z 448 (M+H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:33])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[C@@H:30]([OH:32])[CH3:31])[N:9]=3)[CH2:2]1.CCN(C(C)C)C(C)C.[C:43](Cl)(=[O:47])[CH:44]([CH3:46])[CH3:45]>C1COCC1>[OH:32][C@H:30]([C:22]1[N:21]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:6]([CH2:5][CH:3]4[CH2:4][N:1]([C:43](=[O:47])[CH:44]([CH3:46])[CH3:45])[CH2:2]4)[N:7]3[CH3:33])=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:31]
Reactant: CC(C)C(=O)Cl
Reactant: C[C@H](O)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)N1CC(Cc2nc3c(N4CCOCC4)nc(-n4c([C@H](C)O)nc5ccccc54)nc3n2C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.5 %

Procedure:
To a solution of (S)-1-[1-(8-azetidin-3-ylmethyl-9-methyl-6-morpholin-4-yl-9H-purin-2-yl)-1H-benzoimidazol-2-yl]ethanol (70 mg, 0.16 mmol) in THF (2 mL) was added DIPEA (30 μL, 0.17 mmol) and isobutyryl chloride (17 μL, 0.16 mmol) and the resulting mixture stirred at r.t. for 1 h. The reaction mixture was partitioned between DCM and sat. aq. NaHCO3, the organic phase dried (phase separator) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-30%) then (Si-PCC, MeOH:DCM, 0-8%) affording 859 (22 mg, 27%). LCMS (method I): RT 3.46 min, [M+H]+ 519.3. 1H NMR (DMSO, 400 MHz): δ 7.95-7.95 (1 H, m), 7.70-7.69 (1 H, m), 7.30-7.26 (2 H, m), 5.59-5.57 (1 H, m), 5.39 (1 H, d, J=6.33 Hz), 4.39-4.10 (4 H, brd s), 4.34 (1 H, t, J=8.25 Hz), 4.02 (1 H, t, J=8.79 Hz), 3.95 (1 H, dd, J=8.47, 5.27 Hz), 3.80-3.75 (4 H, m), 3.72 (3 H, s), 3.67-3.65 (1 H, m), 3.27-3.21 (3 H, m), 2.48-2.39 (1 H, m), 1.60 (3 H, d, J=6.48 Hz), 0.98 (3 H, d, J=1.76 Hz), 0.96 (3 H, d, J=1.78 Hz)
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([Br:12])=[CH:10][C:9]([F:13])=[CH:8][C:7]=1Br)(=[O:3])[CH3:2].[C:15]1(=[O:28])[C:20]2[CH:21]=[C:22]3[N:27]([C:19]=2[CH2:18][CH2:17][NH:16]1)[CH2:26][CH2:25][CH2:24][CH2:23]3.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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].O1CCOCC1>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:16]2[CH2:17][CH2:18][C:19]3[N:27]4[C:22]([CH2:23][CH2:24][CH2:25][CH2:26]4)=[CH:21][C:20]=3[C:15]2=[O:28])=[CH:8][C:9]([F:13])=[CH:10][C:11]=1[Br:12])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(Br)cc(F)cc1Br
Reactant: O=C1NCCc2c1cc1n2CCCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)OCc1c(Br)cc(F)cc1N1CCc2c(cc3n2CCCC3)C1=O
Temperature: 100 °C
Yield: 48.4 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (60 mL), 101c (1.9 g, 6.0 mmol), 101g (400 mg, 2.0 mmol), and cesium carbonate (1.3 g, 4.0 mmol). After bubbling nitrogen through the resulting mixture for 30 minutes, Xantphos (120 mg, 0.2 mmol) and tris(dibenzylideneacetone)dipalladium(0) (180 mg, 0.2 mmol) were added, and the reaction mixture was heated at 100° C. for 12 h. After this time the reaction was cooled to room temperature, partitioned between ethyl acetate (40 mL) and water (40 mL), and filtered. The aqueous layer was separated and extracted with ethyl acetate (70 mL×3). The combined organic layer was washed with brine (30 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified on flash column eluting with 2:1 PE/EA to afford 101h (421 mg, 46%) as yellow solid. MS: [M+H]+ 435. 1H NMR (500 MHz, MeOD) δ 7.52-7.50 (m, 1H), 7.20-7.23 (m, 1H), 6.14 (s, 1H), 5.10-5.20 (m, 2H), 4.06-4.12 (m, 1H), 3.92-3.97 (m, 1H), 3.83-3.88 (m, 1H), 3.75-3.79 (m, 1H), 3.03-3.10 (m, 1H), 2.94-2.99 (m, 1H), 2.75-2.83 (m, 2H), 2.00-2.05 (m, 5H), 1.83-1.88 (m, 2H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][OH:12])[NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:15]I>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][OH:12])[N:8]([CH3:15])[C:5]2=[N:6][CH:7]=1
Reactant: CI
Reactant: OCc1nc2cc(Br)cnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(CO)nc2cc(Br)cnc21

Procedure:
A procedure similar to that described in Preparation 15 was repeated, except that the reaction was conducted using 3.00 g of 6-bromo-2-hydroxymethyl-3H-imidazo-[4,5-b]pyridine (prepared as described in Preparation 58), 0.58 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 0.92 ml of methyl iodide and 60 ml of dimethylformamide. After completion of the reaction with methyl iodide, the reaction mixture was freed from dimethylformamide by distillation under reduced pressure. The residue was diluted with water, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 50:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 1.40 g of the title compound, melting at 142°-144° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[CH2:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH2:13]=[C:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10]1
Reactant: O=C([O-])[O-]
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=C1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
To a mixture of (S)-1-(tert-butoxycarbonyl)-4-methylenepyrrolidine-2-carboxylic acid (35 g, 154 mol) in DMF (155 mL) was added potassium carbonate (32 g, 1.5 eq) at room temperature. The mixture was stirred at room temperature for 1 hr before being cooled with a water bath. Methyl iodide (19.2 mL, 2 eq) was added dropwised. The mixture was stirred at room temperature for 6 hr. The reaction mixture was filtered through a pad of celite, diluted with ethyl acetate (300 mL), washed with water (200 mL). The aqueous layer was extracted with ethyl acetate (300 and 200 mL). The combined organic layers were washed with 10% Na2S2O3 solution (100 mL), water (3×200 mL) and brine, dried (Na2SO4), filtered and evaporated to dryness. The residue was passed through a silica gel (2 wt. volumes) pad with 0-15% ethyl acetate in hexanes to afford the title compound (37.06 g, quantitative yield) as a colorless oil. 1H NMR (500 MHz, CDCl3): 5.03 and 4.99 (2 br s, 2H), 4.51 (dd, J=9.5, 2.7 Hz) and 4.40 (dd, J=9.5, 3.3 Hz, 1H), 4.09 and 4.06 (2 br s, 2H), 3.73 (s, 3H), 3.01-2.92 (m, 1H), 2.65-2.60 (m, 1H), 1.47 and 1.42 (2 s, 9H).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6]C(S(OC)(=O)=O)=CC=1.CCO/C=[C:17]1\[C:18]([O:20][C:21]([C:23]2[CH:28]=CC=CC=2)=[N:22]\1)=O>C(#N)C>[CH3:28][CH2:23][CH:21]1[O:20][CH2:18][CH2:17][N:22]1[C:2]1([CH2:7][CH3:6])[O:20][CH2:18][CH2:17][N:22]1[C:21]1([CH2:23][CH3:28])[O:20][CH2:18][CH2:17][NH:22]1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CCO/C=C1/N=C(c2ccccc2)OC1=O
Solvent: CC#N
Product: CCC1OCCN1C1(CC)OCCN1C1(CC)NCCO1

Procedure:
Loading amount: acetonitrile (36 mL), methyl p-tosylate (0.3 mmol, 0.045 mL), EtOx (96 mmol, 9.7 mL), Yield: 7 g, Degree of polymerization (DP)=302, Polydispersity index (PDI: Mw/Mn)=1.1)
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[N:5][N:4]2[CH2:8][CH2:9][CH2:10][C:3]=12.[CH3:11][O:12][C:13](=[O:31])[C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=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>[CH3:11][O:12][C:13](=[O:31])[C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16]([C:2]2[C:6]([CH3:7])=[N:5][N:4]3[CH2:8][CH2:9][CH2:10][C:3]=23)[CH:15]=1
Reactant: COC(=O)c1ccc(C#N)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1nn2c(c1Br)CCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C#N)c(-c2c(C)nn3c2CCC3)c1
Temperature: 95 °C
Yield: 49.8 %

Procedure:
In a pressure sealed flask a suspension of 3-bromo-2-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (1.01 g, 5.0 mmol), 4-cyano-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (1.8 g, 6.25 mmol), and K3PO4 (2.65 g, 12.5 mmol) in dioxane (50 mL) was degassed by bubbling N2 for 30 m at room temperature. After the addition of tetrakis(triphenylphosphine)palladium (0.58 g, 0.5 mmol) the reaction flask was sealed and the contents heated to 95° C. for 5 h. After cooling the reaction mixture was diluted several fold with EtOAc, and washed with dilute aqueous NaHCO3 followed by brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified over normal phase silica starting with 100% DCM for 5 m and then increasing to 10% MeOH in DCM over 25 m to give the desired product as a yellow solid (0.70 g, 2.49 mmol). MS m/z 282.5 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:6][N:7]([C:28]1[N:33]=[CH:32][C:31](Br)=[CH:30][N:29]=1)[CH:8]([C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[N:20]([CH2:24][CH:25]1[CH2:27][CH2:26]1)[CH2:21][CH2:22][CH3:23])[CH3:9].CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[NH:71]1[CH2:76][CH2:75][CH:74]([C:77]([O:79][CH2:80][CH3:81])=[O:78])[CH2:73][CH2:72]1>C1(C)C=CC=CC=1.[Cl-].[Na+].O.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:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:6][N:7]([CH:8]([C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[N:20]([CH2:24][CH:25]1[CH2:27][CH2:26]1)[CH2:21][CH2:22][CH3:23])[CH3:9])[C:28]1[N:33]=[CH:32][C:31]([N:71]2[CH2:76][CH2:75][CH:74]([C:77]([O:79][CH2:80][CH3:81])=[O:78])[CH2:73][CH2:72]2)=[CH:30][N:29]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1C(C)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1C(C)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCC(C(=O)OCC)CC2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-{1-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-phenyl]-ethyl}-amine (200 mg) is dissolved in toluene (3 ml), and thereto are added tris(dibenzylideneacetone)dipalladium (27 mg), sodium tert-butoxide (42 mg), 2-(di-tert-butylphosphino)biphenyl (35 mg) and ethyl piperidine-4-carboxylate (66 μl) and the mixture is stirred at room temperature under nitrogen flow overnight. To the reaction solution are added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (hexane:ethyl acetate=19:1→21:4) to give ethyl 1-[2-((3,5-bis-trifluoromethyl-benzyl)-{1-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-phenyl]-ethyl}-amino)-pyrimidin-5-yl]-piperidine-4-carboxylate (78 mg). MS (m/z): 760 [M+H]+
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.Cl.[CH2:16](O)[CH:17]=C>>[OH:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH2:12][CH:16]=[CH2:17])=[O:10])=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(CO)cc1
Reactant: C=CCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: C=CCOC(=O)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93 %

Procedure:
To an alkoxide solution prepared from sodium hydride (60% in oil, 1.60 g, 40.0 mmol) and allyl alcohol (100 mL) was added methyl 4-hydroxymethylbenzoate (3.32 g, 20.0 mmol) under ice-cooling. The resulting mixture was stirred at room temperature for 6 h, adjusted with 1N hydrochloric acid to pH 3, and then concentrated under reduced pressure. To the residue was added ethyl acetate (150 mL), and the mixture was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was separated and purified by silica gel column chromatography (hexane-ethyl acetate, 5:2) to give 3.59 g (93%) of allyl 4-hydroxymethylbenzoate as a pale-yellow oil.