Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:3]=1[C:13]([NH2:15])=[O:14].N1C=CC=CC=1.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>O1CCCC1>[C:26]1([O:25][C:23](=[O:24])[NH:1][C:2]2[S:6][N:5]=[C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:3]=2[C:13](=[O:14])[NH2:15])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCCCCSc1nsc(N)c1C(N)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCSc1nsc(NC(=O)Oc2ccccc2)c1C(N)=O
Reaction time: 3 h
Yield: 79 %

Procedure:
To a solution of 5-amino-3-pentylsulfanyl-isothiazole-4-carboxylic acid amide (2.2 g, 9.0 mmol) in 36 mL of tetrahydrofuran was added pyridine (0.90 g, 11 mmol) and phenyl chloroformate (1.7 g, 11 mmol). After stirring for 3 hours, additional pyridine (0.15 g, 1.9 mmol) and phenyl chloroformate (0.29 g, 1.9 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, diluted with water and extracted 2× with CH2Cl2, 1× with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated for 12 hours with ether-hexane, and the resulting solids were collected and dried in vacuo, affording 2.6 g (79%) of (4-carbamoyl-3-pentylsulfanyl-isothiazol-5-yl)-carbamic acid phenyl ester as a colorless solid. 1H NMR (300 MHz, CDCl3) δ7.41 (t, 2H, J=7.3 Hz), 7.29-7.20 (m, 3H), 3.31 (t, 2H, J=7.3 Hz), 1.72 (m, 2H), 1.50-1.30 (m, 4H), 0.90 (t, 3H, J=7.1 Hz) ppm; MS (APCI, m/z): 366 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:24])=[CH:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.N1C=CC=CC=1.[CH3:31][C:32](OC(C)=O)=[O:33]>O1CCOCC1.CN(C1C=CN=CC=1)C>[F:1][C:2]([F:24])=[CH:3][CH2:4][N:5]([C:6]1[CH:7]=[C:8]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:32](=[O:33])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: FC(F)=CCNc1cc(OCc2ccccc2)c2ccccc2c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC(=O)N(CC=C(F)F)c1cc(OCc2ccccc2)c2ccccc2c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 95.9 %

Procedure:
A solution of 210 (149 mg, 0.46 mmol) in dioxane (5 mL) under Ar was treated with DMAP (50 mg, 0.40 mmol), pyridine (0.37 mL, 4.6 mmol) and Ac2O (0.2 mL, 2.3 mmol) and stirred at 25° C. for 19 h. The reaction solution was quenched by the addition of 10% aqueous HCl (10 mL) and EtoAc (10 mL). The aqueous layer was removed and extracted with EtOAc (3×5 mL). The organic solutions were combined, washed with saturated aqueous NaCl (15 mL), dried (MgSO4), and concentrated under reduced pressure. Chromatography (SiO2, 15% EtOAc-hexane) afforded 211 (162 mg, 169 mg theoretical, 96%) as a pale yellow oil: 1H NMR (CDCl3, 400 MHz) δ8.33 (dd, 1H, J=1.6, 8.1 Hz, C8-H), 7.77 (dd, 1H, J=1.7, 7.5 Hz, C5-H), 7.52 (m, 5H, C6H5), 7.38 (m, 2H, C6 and C7-H), 7.20 (d, 1H, J=1.6 Hz, C4-H), 6.57 (d, 1H, J=1.6 Hz, C2-H), 5.25 (s, 2H, CH2Ph), 4.43 (dtd, 1H, J=1.9, 7.9, 24.8 Hz, C2'-H), 4.32 (dd, 1H, J=1.6, 1.6 Hz, C1'-H), 4.30 (m, 1H, C1'-H), 1.82 (s, 3H, CH3CO); 13C NMR (CDCl3, 100 MHz) δ170.0, 160.0, 157.1, 155.1, 139.4, 135.9, 133.8, 128.2, 127.7, 127.2, 127.1, 126.9, 125.7, 124.7, 121.9, 118.6, 105.0, 74.9 (dd, J=75.2, 91.6 Hz), 69.8, 41.8 (d, J=28 Hz), 22.0; 19F NMR (CDCl3, 376 MHz) δ-87.0 (d, J=40.0 Hz), -89.1 (dd, J=24.8, 40.0 Hz); IR (film) vmax 2928, 1745, 1660, 1413 cm-1 ; FABHRMS (NBA-NaI) m/z 368.1740 (M+H+, C22H19F2NO requires 368.1470).
Reaction SMILES: [CH2:1]([N:8]([CH3:25])[C:9]([CH2:11][CH2:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]([OH:24])[C:21]([OH:23])=[O:22])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CS(C)=O>O>[CH2:32]([O:22][C:21](=[O:23])[CH:20]([C@@H:16]1[CH2:17][CH2:18][CH2:19][N:15]1[C:13](=[O:14])[CH2:12][CH2:11][C:9](=[O:10])[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:25])[OH:24])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(O)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (2RS)-2-[(2S)-1-[3-(N-benzyl-N-methlcarbamoyl)propanoyl]pyrrolidin-2-yl]-2-hydroxyacetic acid (134 mg), potassium carbonate (64 mg), benzyl bromide (51 μl) and DMSO (1 ml) was stirred for 1 hr at room temperature. Water was added to the mixture. The mixture was extracted with a mixture of hexane and EtOAc (1:1). The extract was washed, dried and evaporated. The residue was purified by column chromatography on silica gel (hexane-EtOAc) to give the title compound (141 mg) having the following physical data:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.[Cl:12][C:13]1[CH:14]=[C:15](I)[N:16]2[C:21]=1[CH:20]=[N:19][C:18]([S:22][CH3:23])=[N:17]2.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.O1CCOCC1>[Cl:12][C:13]1[CH:14]=[C:15]([C:6]2[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:16]2[C:21]=1[CH:20]=[N:19][C:18]([S:22][CH3:23])=[N:17]2
Reactant: COc1ccc(B(O)O)cn1
Reactant: CSc1ncc2c(Cl)cc(I)n2n1
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: C1COCCO1
Product: COc1ccc(-c2cc(Cl)c3cnc(SC)nn23)cn1
Temperature: 60 °C
Yield: 81 %

Procedure:
2-Methoxypyridine-5-boronic acid (116 mg, 0.758 mmol), Tetrakis(triphenylphosphine)palladium(0) (46 mg, 0.040 mmol) and 5-Chloro-7-iodo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.152 g, 0.467 mmol) were placed in a vial, followed by 1,4-Dioxane (3.00 mL) and 2.00 M of Sodium carbonate in Water (1.00 mL, 2.00 mmol). The sample was frozen, placed under vacuum, sealed, warmed, refrozen, evacuated, then placed under nitrogen and heated in a 60° C. block. When complete, the sample was partitioned between EtOAc and water (30 mL each), the aq. extracted (EtOAc 3×20 mL) and the comb. organics washed with brine. Purification (ISCO, 12 g, 0-30% EtOAc:Hex) afforded 5-Chloro-7-(6-methoxy-pyridin-3-yl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.116 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH2:10]([O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH3:13].Cl.[OH-].[Na+]>CC(C)=O.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:21][CH:20]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: CCCCOc1ccc(N)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCCOc1ccc(Nc2nc(Cl)ncc2F)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of 2,4-dichloro-5-fluoropyrimidine (0.5 g, 3.0 mmol) and 4-n-butoxyaniline (0.49 g, 3 mmol) in acetone/H2O (1:9 mL) at room temperature was added concentrated HCl (0.1 mL). The mixture was heated at reflux for 1 h, cooled to room temperature, and made basic with 2 N NaOH (2 mL). The aqueous layer was extracted with EtOAc (2×50 mL) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The crude black solid was purified by chromatography (4:1 hexanes/EtOAc) to afford 2-chloro-N4-(4-n-butyloxyphenyl)-5-fluoro-4-pyrimidineamine (0.71 g, 80%) as a brown oil: 1H NMR (300 MHz, CDCl3) δ 8.01 (d, J=2.7 Hz, 1H), 7.51-7.46 (m, 2H), 6.95-6.89 (m, 2H), 6.83 (bs, 1H), 3.99-3.95 (t, J=6.5 Hz, 2H), 1.82-1.57 (m, 2H), 1.53-1.43 (m, 2H), 0.98 (t, J=7.2 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].C(N(CC)CC)C.[CH3:22][N:23]([CH3:27])[C:24](Cl)=[S:25]>ClCCl>[C:12]([C:3]1[CH:4]=[CH:5][C:6]([O:11][C:24](=[S:25])[N:23]([CH3:27])[CH3:22])=[C:7]([CH2:8][CH2:9][CH3:10])[C:2]=1[OH:1])(=[O:14])[CH3:13]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CN(C)C(=S)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1c(OC(=S)N(C)C)ccc(C(C)=O)c1O
Yield: 41.4 %

Procedure:
Stir a mixture of 1-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (2 g, 10.3 mmol), triethylamine (1.6 mL 11.3 mmol), and dichloromethane (40 mL) at room temperature. Add dimethylthiocarbamoyl chloride (1.27 g, 10.3 mmol) and stir at room temperature overnight. Wash the mixture with 1M hydrochloric acid (25 mL), dry over magnesium sulfate, filter and concentrate. Purify the residue via silica chromatography eluting with hexanes to 7:3 hexanes:ethyl acetate to afford dimethyl-thiocarbamic acid O-(4-acetyl-3-hydroxy-2-propyl-phenyl) ester (1.2 g, 41%) as a light yellow solid. Stir the yellow solid in tetradecane (10 mL) at 250° C. for an hour and purify by silica chromatography eluting with hexanes to 6:4 hexanes:ethyl acetate to give the title compound (1.08 g, 90%) as a white solid. LCMS (m/z) 280 M−1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.N#N.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>C1COCC1.CCN(CC)CC.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.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccnc(Cl)n1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
To a mixture of Pd(PPh3)2Cl2 (0.9 g) and PPh3 (0.7 g) in THF (200 mL) and Et3N (300 mL) was added 2,4-dichloropyrimidine (40 g, 0.27 mol) under a stream of N2. After bubbling N2 into the solution for 15 min, CuI (0.5 g) was added, followed by (trimethylsilyl)acetylene (29 g, 0.29 mol). The mixture was heated at reflux for 4.5 h. The mixture was cooled to rt and filtered, washing with EtOAc. The filtrated was concentrated and the residue was diluted with hexanes (500 mL) and loaded directly onto a short pad of SiO2. The product was eluted with 10% EtOAc/hexanes to provide a light orange solid (49.3 g), which was used without further purification. TLC: Rf=0.42. mp 51-54° C. IR: 3125 (w), 2961 (w), 1557 (s), 1523 (s). 1H NMR: 8.58 (d, J=5.0 Hz, 1H), 7.30 (d, J=5.0 Hz, 1H), 0.28 (s, 9H). 13C NMR: 162.23, 160.16, 153.41, 122.52, 104.23, 100.75, 0.01. Anal. Calcd for C9H11ClN2Si: C, 51.29; H, 5.26; N, 13.29. Found: C, 51.45; H, 5.16; N, 13.33.
Reaction SMILES: F[C:2](F)(F)C(O)=O.C([Zn]CC)C.ICI.[I:16][C:17](=[CH2:37])[CH2:18][C@H:19]([CH2:28][O:29][Si:30]([CH3:36])([CH3:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[O:20][Si:21]([CH3:27])([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>ClCCCl>[I:16][C:17]1([CH2:18][C@H:19]([CH2:28][O:29][Si:30]([CH3:36])([CH3:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[O:20][Si:21]([CH3:27])([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:2][CH2:37]1
Reactant: O=C(O)C(F)(F)F
Reactant: C=C(I)C[C@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: CC[Zn]CC
Solvent: ICI
Solvent: ClCCCl
Product: CC(C)(C)[Si](C)(C)OC[C@@H](CC1(I)CC1)O[Si](C)(C)C(C)(C)C
Reaction time: 0.58 h
Yield: 76.7 %

Procedure:
Trifluoroacetic acid (TFA; 281 mg, 2.47 mmol) was added to a solution of diethyl zinc (ZnEt2, 2.5 mL, 2.5M in hexane) in DCE (1 mL) at 0° C. and stirred for 35 mins. Diiodomethane (CH2I2, 66 mg, 2.5 mmol) was then added at 0° C., and the mixture stirred for an additional 20 min. A solution of (R)-5-(2-iodoallyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane (step D; 188 mg, 0.41 mmol) in DCE (2 ml) was added and the reaction stirred at room temperature overnight. The reaction was then quenched by addition of a mixture of methanol (5 mL) and brine (0.5 mL). After stirring for an additional hour, the mixture was concentrated under reduced pressure. The crude material was extracted with aq. NH4Cl/CHCl3 and the organic layer washed with brine, dried (MgSO4) and concentrated under reduced pressure. The crude material was triturated in hexane and the solution filtered and evaporated to afford (R)-5-((1-iodocyclopropyl)methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane (148 mg, 77%).
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na].[C:10](Cl)(=[O:14])[C:11]([CH3:13])=[CH2:12]>C1(C)C=CC=CC=1.C1C=CC=CC=1>[C:10]([N:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:8])(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: C=C(C)C(=O)Cl
Reactant: O=C1CCCCCN1
Agent: [Na]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)N1CCCCCC1=O

Procedure:
74 g of ε-caprolactam in 700 ml dry toluene is heated with 9.5 g of sodium at 90°-95° C. When all of the sodium metal has reacted, 43 ml of methacryloyl chloride in 50 ml dry benzene is added dropwise into the voluminous caprolactam salts at 4°-6° C. The mixture is then poured into a separatory funnel, washed with 200 ml water, 200 ml of sodium dicarbonate solution, and again with 20 ml water. The organic compounds are extracted with ether from the water phase, and the ether solution and benzene solution are dried over CaCl2 and the solvent evaporated under reduced pressure. The product, N-methacryloylcaprolactam, comes off at 90° C./2 mm hg. The yield is 32.3 g (42.8% based on sodium).
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[NH:11][C:12](=[NH:19])[CH:13]=[CH:14][C:15]=2[CH2:16]OC)[N:9]=1)[NH2:3].[S:20]([NH2:24])([NH2:23])(=[O:22])=[O:21].O>COCCO>[NH2:19][C:12]1[N:11]=[C:10]([C:8]2[N:9]=[C:5]([N:4]=[C:2]([NH2:3])[NH2:1])[S:6][CH:7]=2)[C:15]([CH:16]=[N:23][S:20]([NH2:24])(=[O:22])=[O:21])=[CH:14][CH:13]=1
Reactant: COCc1ccc(=N)[nH]c1-c1csc(N=C(N)N)n1
Reactant: NS(N)(=O)=O
Solvent: O
Solvent: COCCO
Product: NC(N)=Nc1nc(-c2nc(N)ccc2C=NS(N)(=O)=O)cs1
Reaction time: 3 h
Yield: 49.8 %

Procedure:
A mixture of 2-(diaminomethyleneamino)-4-[6-(imino)(methoxy)methylpyridin-2-yl]thiazole (2.1 g) and sulfamide (2.9 g) in 2-methoxyethanol (10.5 ml) was stirred for 3 hours at 70°-75° C. The mixture was added to water, isolated precipitate was collected by filtration and dried. The precipitate was recrystallized from a mixture of N,N-dimethylformamide and ethyl acetate to give 4-[6-(amino)(aminosulfonylimino)methylpyridin-2-yl]-2-(diaminomethyleneamino)thiazole (1.28 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[OH:11][C:12]1[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[C:16]([CH:19]=1)[CH:17]=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][C:12]2[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[C:16]([CH:17]=[O:18])[CH:19]=2)[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: COc1ccc(O)cc1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2cc(Cl)ccc2C#N)cc1C=O
Yield: 90 %

Procedure:
4-Chloro-2-fluorobenzonitrile (0.60 g, 3.9 mmol), 5-hydroxy-2-methoxybenzaldehyde (0.59 g, 3.9 mmol) and cesium carbonate (1.26 g, 3.9 mmol) were heated with stirring in dry DMF (4 ml) at 50° C. for 17 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water, 10% aqueous sodium carbonate (2×), water (2×), brine and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(3-formyl-4-methoxy-phenoxy)-benzonitrile (1.01 g, 90%) as a yellow solid.
Reaction SMILES: B(F)(F)F.CCOCC.[Cl:10][C:11]1[CH:20]=[CH:19][C:14]([O:15][CH2:16][CH:17]=[O:18])=[C:13]([CH3:21])[CH:12]=1.[CH3:22][NH:23][C:24](=[O:27])[CH2:25]O>O1CCCC1>[Cl:10][C:11]1[CH:20]=[CH:19][C:14]([O:15][CH2:16][CH:17]2[N:23]([CH3:22])[C:24](=[O:27])[CH2:25][O:18]2)=[C:13]([CH3:21])[CH:12]=1
Reactant: CNC(=O)CO
Reactant: Cc1cc(Cl)ccc1OCC=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1OCC1OCC(=O)N1C
Reaction time: 24 h
Yield: 11 %

Procedure:
4.6 g (0.0325 mole) of boron trifluoride etherate was added to a solution containing 4.6 g (0.025 mole) of (4-chloro-2-methylphenoxy)acetaldehyde and 2.5 g (0.028 mole) of N-methylglycolamide in 40 ml of tetrahydrofuran. After 24 hours at ambient temperature, the reaction mixture was concentrated under reduced pressure, extracted with ether, washed with water and dried. Purification by silica chromatography gave 0.7 g of 2-(4-chloro-2-methylphenoxymethyl)-3-methyl-4-oxazolidinone as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:30])[C:17]([Cl:23])=[CH:18][CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C(O)C.C(OCC)(=O)C.[Pt](=O)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:30])[C:17]([Cl:23])=[CH:18][CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3ccc(Cl)c(-c4ccccc4Cl)c3O2)cc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3ccc(Cl)c(-c4ccccc4Cl)c3O2)cc1
Yield: 98.1 %

Procedure:
Treatment of ((2R)-7-chloro-8-(2-chlorophenyl)-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate (2.13 g, 4.62 mmol) in ethanol (100 mL) and ethyl acetate (15 mL) with platinum (IV) oxide (84% Pt, 0.50 g) according to the procedure described for Example 69, Step 8 provided 2.10 g (96%) of ((2R)-7-chloro-8-(2-chlorophenyl)chroman-2-yl)methyl 4-methylbenzenesulfonate as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2](=C)[CH2:3][C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1.I([O-])(=O)(=O)=[O:16].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[O:16]=[C:2]([CH3:1])[CH2:3][C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1
Reactant: C=C(C)Cc1ccc2c(c1)COC2=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Cc1ccc2c(c1)COC2=O
Reaction time: 0.17 h

Procedure:
To a solution of 5-(2-methylprop-2-en-1-yl)-2-benzofuran-1(3H)-one (175 mg, 0.930 mmol) in THF was added osmium tetroxide (295 mg, 0.0460 mmol) and the mixture was stirred for 10 minutes. Then a solution of sodium periodate (497 mg, 2.32 mmol) in water was added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, diluted with DCM, and washed with Na2S2O3 solution. The organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by flash chromatography (30% ether/hexanes) to afford the title compound. LC-MS (IE, m/z): 191.3 [M+1]+.
Reaction SMILES: C([NH:4][C@@:5]1([C:22](NC(C)(C)C)=[O:23])[CH2:9][CH2:8][CH2:7][C@H:6]1[CH2:10][CH2:11][CH2:12][B:13]1[O:17]C(C)(C)C(C)(C)[O:14]1)(=O)C.[OH2:29]>Cl>[NH2:4][C@@:5]1([C:22]([OH:23])=[O:29])[CH2:9][CH2:8][CH2:7][C@H:6]1[CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17]
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CCC[C@H]1CCCB1OC(C)(C)C(C)(C)O1
Reactant: O
Agent: Cl
Product: N[C@@]1(C(=O)O)CCC[C@H]1CCCB(O)O
Temperature: 90 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A stirred mixture of (1S,2R)-1-acetamido-N-tert-butyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)cyclopentanecarboxamide (0.627 g, 1.59 mmol) in 6 N HCl (15 mL) was heated to 90° C. for 20 h, cooled to room temperature, and diluted with water (15 mL). The mixture was extracted with dichloromethane (2×15 mL) and concentrated. Water (20 mL) was then added to the concentrated crude mixture and the aqueous solution is re-concentrated in vacuo (2×) to remove excess HCl. The resulting residue was dissolved in methanol (5 mL) and diluted to a volume of 40 mL with ether and stirred for 1 hour, to remove solid tertbutylamine hydrochloride by filtration. The resultant filtrate, upon concentration was treated with a solution of concentrated ammonium hydroxide (15 mL), followed by removal of the excess ammonium hydroxide under vacuum (3×). The resulting solid white residue was triturated using acetonitrile and dried to afford the target compound (1S,2R)-1-amino-2-(3-boronopropyl)cyclopentanecarboxylic acid (0.397 g, 93%) as a white powder that exists as a 1:1 mixture of the cyclized and uncyclized forms. 1H NMR (DMSO, 300 MHz) δ 6.38 (br d, J=11.4 Hz, NH, 0.5 H), 5.97 (br d, J=12 Hz, NH, 0.5 H), 2.22-2.05 (m, 1 H), 1.98-1.42 (m, 6 H), 1.43-1.00 (m, 3 H), 0.95-0.88 (m, 1 H), 0.60-0.42 (m, 1 H), 0.38-0.20 (m, 1 H); MS (+CI): m/z for C9H18BNO4: expected 215.1; found 215.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH:21][C:22]([C:24]4([O:29][CH3:30])[CH2:28][CH2:27][NH:26][CH2:25]4)=[O:23])[CH:19]=3)[NH:14][N:13]=2)=[CH:8][CH:7]=1.Cl[CH2:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[N:52]=[CH:51][CH:50]=[CH:49][N:48]=3)=[C:43]([F:53])[CH:42]=2)[CH2:37][CH2:36]1)=[O:34].C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH:21][C:22]([C:24]4([O:29][CH3:30])[CH2:28][CH2:27][N:26]([CH2:32][C:33]([N:35]5[CH2:40][CH2:39][N:38]([C:41]6[CH:46]=[CH:45][C:44]([C:47]7[N:48]=[CH:49][CH:50]=[CH:51][N:52]=7)=[C:43]([F:53])[CH:42]=6)[CH2:37][CH2:36]5)=[O:34])[CH2:25]4)=[O:23])[CH:19]=3)[NH:14][N:13]=2)=[CH:8][CH:7]=1
Reactant: COCCOc1ccc(-c2n[nH]c3ccc(NC(=O)C4(OC)CCNC4)cc23)cc1
Reactant: O=C(CCl)N1CCN(c2ccc(-c3ncccn3)c(F)c2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCOc1ccc(-c2n[nH]c3ccc(NC(=O)C4(OC)CCN(CC(=O)N5CCN(c6ccc(-c7ncccn7)c(F)c6)CC5)C4)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methoxy-pyrrolidine-3-carboxylic acid {3-[4-(2-methoxy-ethoxy)-phenyl]-1H-indazol-5-yl}-amide (10AB) (50 mg, 0.103 mmol, 1 equiv) and 2-Chloro-1-[4-(3-fluoro-4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethanone (7AB) (42 mg, 0.124 mmol, 1.2 equiv) were weighed out in a flask and to it was added N,N-dimethylformamide (3 mL) and diisopropylethylamine (26.6 mg, 36 uL, 0.206 mmol, 2 equiv). The reaction content was stirred at room temperature, overnight.