Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[C:11]3[C:7]([CH:8]=[CH:9][N:10]3[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C([O:23][B:24](OC(C)C)[O:25]C(C)C)(C)C.[Li+].CC([N-]C(C)C)C>C1COCC1>[C:16]([O:15][C:13]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[CH:12]=2)[CH:8]=[C:9]1[B:24]([OH:25])[OH:23])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(C3CC3)cc21
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccc(C3CC3)cc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
To a solution of tert-butyl 6-cyclopropyl-1H-indole-1-carboxylate (1.93 g, 7.51 mmol) and triisopropylborate (2.58 mL, 11.26 mmol) in THF was added LDA (1.5 M in cyclohexane, 7.0 mL, 10.5 mmol) at −78° C. The mixture was stirred at −78° C. for 30 min, quenched with ice water (60 mL) and stirred for 15 min without cooling. The mixture was extracted with ethyl acetate 1:1 in hexane (20 mL). The aqueous layer was acidified with aq. 2 N HCl to pH 5 and then extracted with CH2Cl2 (60 mL). The organic layer was dried over Na2SO4 and concentrated to give 1-(tert-butoxycarbonyl)-6-cyclopropyl-1H-indol-2-ylboronic acid as a solid (2.0 g, 88% yield) that was used in the next step without further purification.
Reaction SMILES: [N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:29])[C:10]([C:26]([OH:28])=[O:27])=[CH:11][N:12]3CC3C=CC(OC)=CC=3OC)=[C:7]([CH3:30])[C:6]=2[F:31])[CH2:4][CH2:3][CH2:2]1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>>[F:31][C:6]1[C:7]([CH3:30])=[C:8]2[C:13](=[N:14][C:5]=1[NH:1][CH2:2][CH2:3][CH2:4][O:36][C:34](=[O:35])[C:33]([F:38])([F:37])[F:32])[NH:12][CH:11]=[C:10]([C:26]([OH:28])=[O:27])[C:9]2=[O:29]
Reactant: COc1ccc(Cn2cc(C(=O)O)c(=O)c3c(C)c(F)c(N4CCC4)nc32)c(OC)c1
Reactant: O=C(O)C(F)(F)F
Product: Cc1c(F)c(NCCCOC(=O)C(F)(F)F)nc2[nH]cc(C(=O)O)c(=O)c12

Procedure:
A solution of Example 62A (0.55 mmol) in trifluoroacetic acid (15 mL) was heated to 80° C. for 16 hours and concentrated. The concentrate was dissolved in dichloromethane, washed with water, and filtered; and the filtrate was concentrated to provide the desired product and a small amount of 6-fluoro-5-methyl-4-oxo-7-(azetidin-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid 7-azetidin-1-yl compound. NMR (300 MHz, DMSO-d6) δ 8.4 (s, 1H), 8.15 (m, 1H), 4.5 (m, 2H), 3.55 (m, 2H), 2.7 (m, 3H), 2.1 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][N:6]([C:9]2[C:13]([NH:14]C(=O)OC(C)(C)C)=[CH:12][N:11]([CH3:22])[N:10]=2)[C:5]1=[O:23].C(OC(=O)C)C.[ClH:30]>>[ClH:30].[NH2:14][C:13]1[C:9]([N:6]2[CH2:7][CH2:8][N:4]([CH2:3][CH2:2][OH:1])[C:5]2=[O:23])=[N:10][N:11]([CH3:22])[CH:12]=1
Reactant: Cn1cc(NC(=O)OC(C)(C)C)c(N2CCN(CCO)C2=O)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cn1cc(N)c(N2CCN(CCO)C2=O)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl (3-(3-(2-hydroxyethyl)-2-oxoimidazolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)carbamate (7.65 g) was added 4M hydrogen chloride ethyl acetate solution (76.5 mL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, to the residue was added methanol (30 mL), and the mixture was stirred for 10 min, and concentrated under reduced pressure to give the title compound (5.21 g).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[CH3:12][O:13][C@H:14]1[CH2:17][C@H:16]([NH2:18])[CH2:15]1.CCN(C(C)C)C(C)C>CC#N.[Pd]>[F:8][C:6]1[CH:7]=[C:2]([NH:18][C@H:16]2[CH2:17][C@H:14]([O:13][CH3:12])[CH2:15]2)[C:3]([NH2:9])=[CH:4][CH:5]=1
Reactant: CO[C@H]1C[C@H](N)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [Pd]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H]1C[C@H](Nc2cc(F)ccc2N)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,4-difluoro-1-nitrobenzene (0.2 mL, 1.7 mmol) in CH3CN (3 mL) were added trans-3-methoxycyclobutylamine (0.18 g, 1.7 mmol) and DIPEA (0.3 mL, 1.7 mmol). The reaction mixture was stirred at RT for 18 h then concentrated in vacuo. The resulting residue was carried to the next step without further purification (0.41 g, quantitative). To a solution of the product thus obtained (1.7 mmol) in EtOAc (15 mL) was added Pd/C (350 mg) and the reaction mixture was stirred at RT for 18 h under a hydrogen atmosphere. The suspension was filtered through a pad of Celite® and the filtrate was concentrated in vacuo to afford the title compound as a dark oil (0.36 g, quantitative). 1H NMR (CDCl3, 300 MHz): δ 6.68-6.59 (1H, m), 6.33 (1H, dt, J=19.6 Hz, 2.7 Hz), 6.18 (1H, dd, J=13.6 Hz, 2.7 Hz), 4.00-3.90 (1H, m), 3.76-3.63 (1H, m), 3.53 (3H, br s), 3.27 (3H, s), 2.49-2.37 (2H, m), 2.36-2.12 (2H, m).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]1COC[CH2:12]1.[CH2:16]([C@H:18]1[O:23][CH2:22][C@@H:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:19]1=[O:37])[CH3:17].ICC>COCCOC>[CH2:16]([C:18]1([CH2:11][CH3:12])[O:23][CH2:22][C@@H:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:19]1=[O:37])[CH3:17]
Reactant: C1CCOC1
Reactant: CC[C@H]1OC[C@@H](c2ccccc2)N(C(=O)OC(C)(C)C)C1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: COCCOC
Solvent: CCI
Product: CCC1(CC)OC[C@@H](c2ccccc2)N(C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a 1 M solution of sodium bis(trimethylsilyl)amide in THF (1.64 mL, 1.64 mmol) at −78° C. was added dropwise a solution of tert-butyl (2R,5R)-2-ethyl-3-oxo-5-phenylmorpholine-4-carboxylate from Step C (500 mg, 1.64 mmol) in DME (25 mL) at −78° C. The resulting mixture was stirred at −78° C. for 10 min then iodoethane (0.131 mL, 1.64 mmol) was added. After stirring at −78° C. for 30 min, then at −30° C. for 30 min, the reaction mixture was cooled to −78° C. and quenched with saturated aqueous NH4Cl (20 mL) then extracted with EtOAc (2×40 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—95:5 to 70:30, to give the title compound. MS: m/z=278 (M−C4H7).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18](SC)[N:17]=3)=[CH:14][N:13]=[C:12]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[N:11]=2)=[CH:5][CH:4]=1.[NH3:31]>O1CCOCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([NH2:31])[N:17]=3)=[CH:14][N:13]=[C:12]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2nc(-c3ccncc3)ncc2-c2nc(C)nc(SC)n2)cn1
Reactant: N
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(-c3ccncc3)ncc2-c2nc(C)nc(N)n2)cn1
Temperature: 100 °C
Yield: 54.4 %

Procedure:
A glass microwave reaction vessel was charged with N-(6-methoxypyridin-3-yl)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)-2-(pyridin-4-yl)pyrimidin-4-amine (8 mg, 0.019 mmol), ammonia (0.5 mL, 23.11 mmol) (30% in water) and dioxane (1 mL). The reaction mixture was stirred and heated in a Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 18 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 10% MeOH/EtOAc to give 4-(4-(6-methoxypyridin-3-ylamino)-2-(pyridin-4-yl)pyrimidin-5-yl)-6-methyl-1,3,5-triazin-2-amine (4 mg, 10.33 μmol, 54.0% yield). 1H NMR (300 MHz, d6-DMSO) δ 11.96 (s, 1H); 8.77 (d, J=5.12 Hz, 1H); 8.59 (s, 1H); 8.21 (dd, J=9.06, 2.34 Hz, 1H); 8.15 (d, J=5.12 Hz, 1H); 7.99 (s, 1H); 7.82 (s, 1H); 6.96 (d, J=8.77 Hz, 1H); 3.90 (s, 2H); 2.45 (s, 3H). m/z (ESI, +ve ion) 388.1 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:15][C:16]1[N:21]=[C:20]2[CH:22]=[C:23]([CH:34]=[O:35])[N:24](S(C3C=CC=CC=3)(=O)=O)[C:19]2=[CH:18][CH:17]=1>CN(C=O)C>[CH2:7]([N:24]1[C:19]2[C:20](=[N:21][C:16]([Cl:15])=[CH:17][CH:18]=2)[CH:22]=[C:23]1[CH:34]=[O:35])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1cc2nc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc2nc(Cl)ccc2n1Cc1ccccc1
Reaction time: 0.25 h
Yield: 102.2 %

Procedure:
K2CO3 (0.39 g, 2.8 mmol) and benzyl bromide (0.12 mL, 1.0 mmol) were added to a solution of 5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carbaldehyde (0.17 g, 0.94 mmol, from Step 1) in DMF (3.6 mL). After 15 minutes, the reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with two portions of water, one portion of brine, then dried over sodium sulfate, filtered and concentrated to afford 0.26 g of crude 1-benzyl-5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carbaldehyde as a yellow solid. Sodium tetrahydroborate (53 mg, 1.4 mmol) was added to a solution of the crude aldehyde in THF (5.0 mL) and EtOH (5.0 mL). After 15 minutes, the reaction mixture was quenched with saturated NH4Cl, and was extracted with EtOAc. The extracts were washed with water followed by brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-40% EtOAc in hexanes afforded purified product as a white solid (0.21 g, 82%). 1H NMR (300 MHz, CDCl3) δ 7.45 (d, J=8.6 Hz, 1H), 7.33-7.25 (m, 3H), 7.06 (d, J=8.6 Hz, 1H), 7.03-6.88 (m, 2H), 6.66 (s, 1H), 5.47 (s, 2H), 4.78 (s, 2H).
Reaction SMILES: Cl[CH:2]=[CH:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[I-:11].[Na+]>CC(C)=O>[I:11][CH:2]=[CH:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: [I-]
Reactant: CCCCCC(=O)C=CCl
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCC(=O)C=CI
Reaction time: 18 h
Yield: 64.5 %

Procedure:
A mixture of 25 g (0.16 moles) of 1-chloro-1-octen-3-one (Example 187) and 35 g (0.23 moles) of sodium iodide in 200 ml of reagent acetone is stirred at the reflux temprature for 18 hours. The cooled mixture is filtered and the mother liquor taken to dryness. The residual oil is dissolved in benzene and the solution is washed with 5% sodium thiosulfate solution, saturated sodium chloride solution, dried and taken to dryness. The residual oil is crystallized from hexane to give 26 g of a white solid, mp 35°-37° C.; λ max 1670, 950 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].I[CH2:11][C:12](=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][CH2:11][C:12](=[O:14])[CH3:13]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: CC(=O)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)CNc1ccc(Cl)cc1Cl
Temperature: 100 °C
Yield: 49.9 %

Procedure:
A mixture of 2,4-dichloroaniline (20.2 g, 0.125 mol), iodoacetone (26.6 g, 0.145 mol) and potassium carbonate (18.1 g, 0.13 mol) in DMF (200 ml) was heated under nitrogen at 100° C. overnight. After cooling to rt, water was added and the mixture extracted with ether (×3). The combined organic extracts were washed with water, dried (Na2SO4), filtered and concentrated. Flash chromatography (Heptane:EtOAc 90:10-80:20) afforded 13.6 g (50%) of the title compound as a brown solid.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:14][C:15]([C:17]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:18]=1[OH:24])=[O:16].O>N1C=CC=CC=1>[C:1]12([C:11]([O:23][C:21]3[CH:22]=[C:17]4[C:18](=[CH:19][CH:20]=3)[O:24][C:11]([C:1]35[CH2:10][CH:5]6[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]6)[CH2:8]3)[CH2:2]5)=[CH:14][C:15]4=[O:16])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: CC(=O)c1cc(O)ccc1O
Solvent: O
Solvent: c1ccncc1
Product: O=C(Oc1ccc2oc(C34CC5CC(CC(C5)C3)C4)cc(=O)c2c1)C12CC3CC(CC(C3)C1)C2
Reaction time: 18 h

Procedure:
4 g 1-adamantoyl chloride are added to a solution of 1.5 g 2,5-dihydroxyacetophenone in dry pyridine. The mixture is stirred for 18 hours at 40°, poured into water and extracted with ethyl acetate. The combined organic layers are washed 3 times with 1 N aqueous hydrochloric acid and subsequently with aqueous sodium carbonate solution, dried over magnesium sulfate and concentrated in vacuo. The crude product is dissolved in dry dimethylformamide and added dropwise at 5° to a suspension of 330 mg of sodium hydride (80% in mineral oil) in dry dimethylformamide. The cooling bath is removed, and the mixture is stirred for 4 hours at room temperature. Then 1.5 ml of acetic acid and 250 ml of water are added, followed by extraction with ethyl acetate. The combined extracts are dried over magnesium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 6/1) to remove starting materials and major by-products. Cyclisation of the resultant 1-[5-(1-adamantoyloxy)-2-hydroxyphenyl]-3-(1-adamantyl)-1,3-propandione is achieved by treatment with 20 ml of 32% aqueous hydrochloric acid in methanol/dioxane. 6-(1-adamantoyloxy)-2-(1-adamantyl)-4H-chromen-4-one is obtained:
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12]([O:14]C)=[O:13])=[O:6])#[N:2].[OH-].[Na+].Cl>COCCOC.O>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12]([OH:14])=[O:13])=[O:6])#[N:2]
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)NCC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: N#CCNC(=O)[C@@H]1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
Methyl trans-2-{[(cyanomethyl)amino]carbonyl}cyclopentanecarboxylate (1.08 g, 5.16 mmol) in ethylene glycol dimethyl ether (6.5 mL) was cooled to 0° C. 2.00 M aqueous sodium hydroxide (2.65 mL) was added and the reaction mixture was stirred at 0° C. for 3.5 h. The pH was adjusted to 5 with 2 M aqueous hydrochloric acid and the reaction mixture was diluted with water. The product was extracted into ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and concentrated to give trans-2-{[(cyanomethyl)amino]carbonyl}cyclopentanecarboxylic acid as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]([C:36](O)=[O:37])([CH3:35])[CH3:34])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[F:70][C:71]1([F:77])[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]([CH3:34])([CH3:35])[C:36]([N:74]2[CH2:75][CH2:76][C:71]([F:77])([F:70])[CH2:72][CH2:73]2)=[O:37])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1
Reactant: FC1(F)CCNCC1
Reactant: CC(C)(Oc1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(Oc1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12)C(=O)N1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.5 %

Procedure:
To a mixture of racemic(2′R, 3R, 4′S)-2′-[5-bromo-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.065 mmol), EDCI (18.7 mg, 0.098 mmol), HOBt (15 mg, 0.098 mmol) and DIPEA (75 mg, 0.6 mmol) in THF (2 mL) was added 4,4-difluoropiperidine hydrochloride (30 mg, 0.195 mmol). The mixture was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (19mg).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[F:6][C:7]([F:25])([F:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:18]2=[N:19][CH:20]=[N:21][C:22](O)=[C:17]2[CH:16]=[N:15]1>>[Cl:3][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:7]([F:25])([F:24])[F:6])[N:15]=[CH:16][C:17]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2c1cnn2-c1ccccc1C(F)(F)F
Product: FC(F)(F)c1ccccc1-n1ncc2c(Cl)ncnc21
Temperature: 100 °C
Reaction time: 4 h
Yield: 84.5 %

Procedure:
Phosphoryl trichloride (34.2 ml, 356.88 mmol) was added to 1-(2-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (Intermediate P2) (5.0 g, 17.84 mmol). The resulting solution was stirred at 100° C. for 4 hours. The mixture was evaporated and the residue added to ice (˜200 g) with vigorous stirring. The mixture was stirred for 30 mins and the solid was collected by filtration washed with water (3×50 mL) and dried by suction. The solid was dissolved in ethyl acetate (250 mL), dried (MgSO4) and evaporated to give the product (4.5 g, 85%). 1H NMR (400 MHz, DMSO) δ 7.75-7.80 (1H, m), 7.88-7.91 (1H, m), 7.95-7.98 (1H, m), 8.05-8.07 (1H, m), 8.79 (1H, s), 8.88 (1H, s); m/z (ESI+) (M+H)+=299; HPLC tR=2.39 min.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[N:5][N:6]([CH2:8][C@@H:9]2[C@H:12]([NH:13][C:14](=[O:30])/[C:15](=[N:22]\[O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])/[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C:11](=[O:31])[N:10]2[S:32]([OH:35])(=[O:34])=[O:33])[N:7]=1.Cl.[N:37]1([C:42](N)=[NH:43])C=CC=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:21][C:18]1[S:19][CH:20]=[C:16](/[C:15](=[N:22]/[O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])/[C:14]([NH:13][C@@H:12]2[C:11](=[O:31])[N:10]([S:32]([OH:35])(=[O:34])=[O:33])[C@@H:9]2[CH2:8][N:6]2[N:5]=[N:4][C:3]([CH2:2][NH:1][C:42]([NH2:43])=[NH:37])=[N:7]2)=[O:30])[N:17]=1
Reactant: N=C(N)n1cccn1
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1nnc(CN)n1)c1csc(N)n1)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1nnc(CNC(=N)N)n1)c1csc(N)n1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 50.4 %

Procedure:
To a solution of 2-(((Z)-(2-(((2R,3S)-2-((5-(aminomethyl)-2H-tetrazol-2-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid (20 mg, 0.038 mmol) and pyrazole-1-carboxamidine hydrochloride (11.6 mg, 0.079 mmol). in DMF (376 μL) was added DIPEA (26.2 μL, 0.150 mmol). After stirring at rt for 12 h the solution was concentrated in vacuo. Toluene was added and it was reconcentrated (3×). The crude residue was purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (11 mg, 45%) as a white powder. LCMS: Rt=0.31 min, m/z=575.2 (M+1) Method 2m_acidic; 1H NMR (500 MHz, DMSO-d6) δ 7.49-7.04 (m, 5H), 6.74 (br s, 1H), 5.26 (br s, 1H), 5.14-5.07 (m, 1H), 4.98-4.90 (m, 1H), 4.65 (br s, 2H), 4.59-4.52 (m, 1H), 1.36 (s, 3H), 1.34 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]([C:25]3[CH:26]=[N:27][NH:28][CH:29]=3)[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]4[CH:29]=[N:28][NH:27][CH:26]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2c(-c3cn[nH]c3)cccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cccc(-c3cn[nH]c3)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]([SiH:5]([CH2:7][CH:8]([CH3:10])[CH3:9])Cl)[CH:2]([CH3:4])[CH3:3].[F:11][C:12]([F:18])([F:17])[S:13]([OH:16])(=[O:15])=[O:14].Cl>>[F:11][C:12]([F:18])([F:17])[S:13]([O:16][Si:5]([O:16][S:13]([C:12]([F:18])([F:17])[F:11])(=[O:15])=[O:14])([CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:15])=[O:14]
Reactant: CC(C)C[SiH](Cl)CC(C)C
Reactant: O=S(=O)(O)C(F)(F)F
Agent: Cl
Product: CC(C)C[Si](CC(C)C)(OS(=O)(=O)C(F)(F)F)OS(=O)(=O)C(F)(F)F
Yield: 72.7 %

Procedure:
An oven-dried 250 mL-RB flask is charged with diisobutylchlorosilane (17.9 g, 0.10 mol). Then trifluoromethanesulfonic acid (45 g, 0.30 mol) is added dropwise. The mixture is heated at 60° C. until no HCl evolves (about 6 hours). The residue is distilled to yield 32 g (73%) of the product as a clear liquid. 1H NMR (500 MHz, CDCl3, in ppm) δ 2.06 (theptat, 2H, J=6.5 Hz, 7.0 Hz), 1.26 (d, 4H, J=7.0 Hz), 1.09 (d, 6H, J=6.5 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:37]1([CH3:49])[CH:42]=[C:41]([CH3:43])[CH:40]=[C:39]([CH3:44])[C:38]=1[S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH:18]=2)[S:45]([C:38]2[C:39]([CH3:44])=[CH:40][C:41]([CH3:43])=[CH:42][C:37]=2[CH3:49])(=[O:47])=[O:46])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc(NCc3cccc(OC4CCCCO4)c3)cc2)cc1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(OC3CCCCO3)c2)c2ccc(OCc3ccccc3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 47.3 %

Procedure:
To a solution of (4-benzyloxy-phenyl)-[3-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (12.7 g, 32.6 mmol) in 25 mL methylene chloride at 0° C. was added triethylamine (14.0 mL, 97.8 mmol), DMAP (0.400 g, 3.27 mmol) and 2-mesitylenesulfonyl chloride (14.3 g, 65.2 mmol). The reaction mixture was stirred at room temperature for 17 hr. The reaction mixture was diluted to a volume of 800 mL with methylene chloride and was washed with water (3×200 mL) and saturated aqueous sodium chloride (1×200 mL). The organic layer was dried (magnesium sulfate), filtered, and concentrated. Medium pressure silica gel chromatography (10% ethyl acetate/hexanes to 25% ethyl acetate/hexanes) afforded 8.82 g of the title compound of Step C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.F[C:13]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:15]([C:14]1[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[CH:13]=1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: O=Cc1cccc(F)c1F
Solvent: CCO
Solvent: O
Product: O=C1CC(c2cccc(F)c2)Oc2ccc(Br)cc21
Yield: 15 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (22.6 g, 0.11 mol), 2,3-difluoro-benzaldehyde (15 g, 0.11 mol) and borax (40.2 g, 0.11 mol) in ethanol (140 mL) and H2O (234 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2-(3-fluorophenyl)chroman-4-one (5.3 g, 15%). 1H-NMR (CDCl3): 2.95 (d, 1H), 3.05 (t, 3H), 5.75 (d, 1H), 6.97 (d, 1H), 7.20 (m, 2H), 7.35 (m, 1H), 7.60 (d, 1H), 8.05 (s, 1H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:11](=[CH2:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>CO>[Si:1]([O:8][C@H:9]([CH3:10])[C@H:11]([CH2:17][NH:25][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: C=C(C(=O)OCC)[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: COc1ccc(CN)cc1
Solvent: CO
Product: CCOC(=O)[C@@H](CNCc1ccc(OC)cc1)[C@@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 48 h
Yield: 109.5 %

Procedure:
To a solution of ethyl 2-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]acrylate (15 g) in methanol (300 ml) was added 4-methoxybenzylamine (8.05 g) at room temperature. After stirring for 2 days, the solvent was removed by evaporation to give crude ethyl (2S,3R)-3-(t-butyldimethylsilyloxy)-2-(4-methoxybenzylaminomethyl)butanoate (25.14 g).