Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13].FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])[O-].[Na+].[Na+].ClC1C=CC(N)=CC=1F>CCOCC.CCCCCC>[Cl:9][C:6]1[CH:5]=[CH:4][C:3]([NH:10][C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])=[CH:2][C:7]=1[F:8]
Reactant: O=C(Nc1ccc(Cl)c(F)c1Br)C(F)(F)F
Agent: Nc1ccc(Cl)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(Nc1ccc(Cl)c(F)c1)C(F)(F)F
Reaction time: 1 h

Procedure:
N-(2-bromo-4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide: 2,2,2-trifluoroacetic anhydride (5.77 mL, 41.2 mmol) was added dropwise to a stirring mixture of sodium carbonate (6.19 g, 58.4 mmol) and 4-chloro-3-fluoroaniline (5.0 g, 34.3 mmol) in Et2O (50 mL) at −10° C. After 1 h, hexane (30 mL) was added and the reaction mixture filtered. The filtrate was washed with ice-water, 10% aq. NaHCO3 solution, and then brine. The organic phase was treated with activated charcoal, dried over sodium sulfate, filtered through a plug of Celite®, and concentrated to give N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide as a white solid. A solution of tert-Butyllithium (1.7M in pentane) (40.4 mL, 68.7 mmol) was added dropwise to N,N,N′,N′-tetramethylethylenediamine (10.37 mL, 68.7 mmol) in THF (60 mL) at −78° C. After 1 h, N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide in THF (40 mL) was added drop-wise to this yellow solution. After stirring for an additional hour, bromine (2.12 mL, 41.2 mmol) was slowly added and the complete mixture stirred for 1.5 h before quenching and neutralized with 1.0N HCl solution (final pH ˜6-7). The mixture was brought to rt, treated with brine (100 mL), and THF evaporated. The aqueous layer was extracted with EtOAc (3×). The combined organic extracts were washed with water, saturated NaHCO3 solution, brine, dried over sodium sulfate, filtered and dry-loaded onto silica gel. Purification by flash chromatography (120 g column; (hexane/EtOAc solvent system) gave Intermediate 7A (3.95 g, 36%) as a slowly solidifying tan solid. 1H NMR (400 MHz, CDCl3) δ: 8.42 (1H, br. s.), 8.13 (1H, dd, J=9.09, 1.77 Hz), 7.43-7.49 (1H, m) ppm.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([N:29]1[N:33]=[N:32][C:31]([CH3:34])=[N:30]1)[CH2:11][S:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:7])=[O:6].C(SCC(OC)CNS(CCC[I:62])(=O)=O)CCCCCCCCCCCCCCC>>[CH2:13]([S:12][CH2:11][CH:10]([N:29]1[N:33]=[N:32][C:31]([CH3:34])=[N:30]1)[CH2:9][NH:8][S:5]([CH2:4][CH2:3][CH2:2][I:62])(=[O:7])=[O:6])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)n1nnc(C)n1
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)n1nnc(C)n1

Procedure:
3-(3-Chloropropylsulfonylamino)-1-hexadecylthio-2-(5-methyl-2H-tetrazol-2-yl)propane IIIh1 is allowed to react and worked up by the same procedure as described in (5). m.p. 50°-51° C. The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:14]([F:21])=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.N1CCCCC1>CO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:16]/[C:15]3[CH:18]=[CH:19][CH:20]=[C:13]([Cl:12])[C:14]=3[F:21])/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Br)cc2N1
Reactant: O=Cc1cccc(Cl)c1F
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(Br)ccc2/C1=C/c1cccc(Cl)c1F
Temperature: 80 °C
Yield: 92.2 %

Procedure:
To the mixture of 6-bromo-2-oxindole (5 g, 24 mmol) (Combi-blocks) and 3-chloro-2-fluorobenzaldehyde (3.7 g, 24 mmol) (Oakwood) in methanol (200 mL) was added piperidine (2 g, 24 mmol) (Aldrich) dropwise. The mixture was then heated at 80° C. for 2 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-6-bromo-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 7.8 g, 94%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:11]([C:20]([O:22][CH3:23])=[O:21])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB(/[CH:38]=[CH:39]/[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)O1.O1CCOCC1>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.O>[C:40]1(/[CH:39]=[CH:38]/[C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:11]([C:20]([O:22][CH3:23])=[O:21])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC1(C)OB(/C=C/c2ccccc2)OC1(C)C
Reactant: COC(=O)[C@@H]1CC[C@H](c2ccc(Br)cc2)N1C(=O)OC(C)(C)C
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: C1COCCO1
Solvent: O
Product: COC(=O)[C@@H]1CC[C@H](c2ccc(/C=C/c3ccccc3)cc2)N1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
In a vial containing 1-(1,1-dimethylethyl) 2-methyl (2S,5R)-5-(4-bromophenyl)-1,2-pyrrolidinedicarboxylate (D78, 100 mg, 0.26 mmol), sodium carbonate (138 mg, 1.30 mmol), 4,4,5,5-tetramethyl-2-[(E)-2-phenylethenyl]-1,3,2-dioxaborolane (90 mg, 0.39 mmol) and Pd(PPh3)4 (30 mg, 0.026 mmol) were added dioxane (2 ml) and water (1 ml). The mixture was stirred for 2 h at 80° C. After cooling, the mixture was extracted with ethyl acetate. The organic layer was filtered by phase separator tube and evaporated. The residue was purified by chromatography on silica gel using cyclohexane/ethyl acetate (1:0 to 9:1) to afford the title compound as a light yellow solid (90 mg, 85%). Rt (HPLC): 7.02 min; MS: (ES/+) m/z: 308 (MH-Boc) C25H29NO4 requires 407.
Reaction SMILES: [F:1][C@@H:2]([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C@@H:20]([O:26]C3CCCCO3)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:14][CH:13]=2)=[N:10][CH:11]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CO>[F:1][C@@H:2]([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[N:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C@@H:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:14][CH:13]=2)=[N:8][CH:7]=1
Reactant: CCCCC[C@@H](COc1ccc(-c2ncc(OCC[C@@H](F)CCCC)cn2)cc1)OC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCCC[C@H](O)COc1ccc(-c2ncc(OCC[C@@H](F)CCCC)cn2)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
In a reaction flask were charged 6.4 g of the compound obtained in step 1 and 485 ml of methanol, followed by cooling to 5° C. A solution of 0.805 g of p-toluenesulfonic acid (monohydrate) in 201.5 ml of methanol was added thereto dropwise at that temperature over 1 hour. After the addition, the reaction temperature was elevated to 20° C., and the mixture was stirred at that temperature until the reaction completed while monitoring the unreacted substance by HPLC. After completion of the reaction, the reaction mixture was neutralized with a sodium hydrogencarbonate aqueous solution, and methanol was removed by distillation under reduced pressure to obtain 7.0 g of a crude product. Purification by silica gel column chromatography furnished 2.87 g of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:19][S:20]([NH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1)(=[O:22])=[O:21]
Reactant: COC(=O)Cc1cccc(N)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Cc1cccc(NS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Methyl 3-aminophenylacetate (2.26 g, 13.7 mmol) was dissolved in dry methylene chloride (20 mL) and cooled to 0° C. Pyridine (2.2 mL, 27.2 mmol) was added followed by dropwise addition of methanesulfonyl chloride (1.3 mL, 16.8 mmol). The mixture was stirred at 0° C. for 1 hour and at room temperature for 3 hours, then poured into 100 mL of saturated sodium bicarbonate solution. The organic layer was washed with saturated sodium bicarbonate (100 mL), 1N HCl (2×100 mL) and brine. Dried over MgSO4. Solvent was evaporated to afford methyl 3-(methanesulfonylamino)phenylacetate. (3.36 g, 100%). 1H NMR (CDCl3) δ 7.32 (1H, dd), 7.2-7.1 (3H, m), 6.57 (1H, s), 3.72 (3H, s), 3.64 (2H, s), 3.02 (3H, s).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]([P:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[NH2:30][OH:31].C[O-].[Na+].Cl>CO>[OH:31][NH:30][C:3](=[O:2])[CH2:4][N:5]([P:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NO
Reactant: COC(=O)CN(CCc1ccccc1)P(=O)(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(CN(CCc1ccccc1)P(=O)(c1ccccc1)c1ccccc1)NO
Reaction time: 16 h
Yield: 25.7 %

Procedure:
N-(Diphenyl phosphinyl)-N-(2-phenylethyl)glycine methyl ester (160 mg, 0.41 mmol) is dissolved in methanol (2.5 mL). To this is added hydroxylamine hydrochloride (57 mg, 0.81 mmol), followed by a 2 mmol of a 25% methanolic solution of sodium methoxide. The reaction is stirred for 16 hours, neutralized with 1N hydrochloric acid and concentrated. The crude product is purified by silica gel flash chromatography to give 41.6 mg (26%) of N-hydroxy-2-[[diphenylphosphinyl](2-phenylethyl)-amino]-acetamide as a colorless solid: MS-IS m/z 395 [M+H]+, 417 [M+Na]+, 433 [M+K]+. (R1 =phenyl ethyl, R2 =H, R3 =phenyl, R4 =phenyl).
Reaction SMILES: N#N.COC1C=CC(C([NH:24][C:25]2[NH:26][C:27](=[O:59])[C:28]3[N:29]=[CH:30][N:31]([CH2:34][O:35][CH:36]([CH2:48][O:49][C:50](=[O:58])[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:37][O:38][C:39](=[O:47])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:32]=3[N:33]=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(O)(=O)C.O>[C:39]([O:38][CH2:37][CH:36]([O:35][CH2:34][N:31]1[CH:30]=[N:29][C:28]2[C:27](=[O:59])[NH:26][C:25]([NH2:24])=[N:33][C:32]1=2)[CH2:48][O:49][C:50](=[O:58])[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])(=[O:47])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCCCC(=O)OCC(COC(=O)CCCCCCC)OCn1cnc2c(=O)[nH]c(NC(c3ccccc3)(c3ccccc3)c3ccc(OC)cc3)nc21
Agent: N#N
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCC(=O)OCC(COC(=O)CCCCCCC)OCn1cnc2c(=O)[nH]c(N)nc21
Yield: 63.2 %

Procedure:
A solution of 0.969 g of N2 -(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-n-octanoyloxy-2-propoxymethyl)guanine in 40 ml of glacial acetic acid plus 10 ml of water was stirred at 75° C. for 3 hours. The solution was then concentrated and the residue chromatographed over silica gel eluting with 1:15 methanol:methylene chloride to give a white solid. The product was recrystallized from methanol to afford 0.385 g of 9-(1,3-di-n-octanoyloxy-2-propoxymethyl)guanine, m.p. 165°-166° C.
Reaction SMILES: [CH:1]1([C:6]([NH:8][CH:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.ClC(=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24]>O1CCCC1>[CH:1]1([C:6]([NH:8][CH:9]([CH2:13][CH3:14])[C:10](=[O:12])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)C(=O)Cl
Reactant: CCC(NC(=O)C1CCCC1)C(=O)O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C(CC)NC(=O)C1CCCC1
Temperature: 25 °C

Procedure:
1.6 g (8 mmol) 2-[(cyclopentylcarbonyl)amino]butanoic acid are suspended in 30 ml tetrahydrofuran and heated to reflux together with 1.91 g (24 mmol) pyridine and a bit of N,N-dimethylaminopyridine. While heating at reflux, 2.19 g (16 mmol) ethyl chloro(oxo)acetate are added dropwise. The reaction mixture is heated at reflux until no more evolution of gas can be observed. After cooling down to room temperature, the reaction mixture is added to ice water and the organic phase extracted with ethyl acetate. The dried organic phase is evaporated to dryness in vacuo, dissolved in ethanol and the solution directly used for the next reaction.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35]C)[CH:30]=1.B(Br)(Br)Br>ClCCl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=1
Reactant: COc1cccc(Cc2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Cc3cccc(O)c3)n(-c3ccccc3)c(=O)c12
Yield: 54 %

Procedure:
(S)-2-(1-((6-Amino-5-(3-methoxybenzyl)pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (70 mg, 0.15 mmol) was treated with boron tribromide (1M in dichloromethane, 436 μl, 0.44 mmol) with dichloromethane as a solvent according to the method described in Example 23. The residue was purified by reverse phase using SP1® Purification System to give 37 mg (54% yield) as a solid. Purity 98%.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]([O:32][CH2:33][CH3:34])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])[O:18][C:19]=2[CH3:20])=[CH:9][C:8]=1[CH3:31])C.[Li+].[OH-]>>[CH2:33]([O:32][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:28])([F:29])[F:30])[O:18][C:19]=2[CH3:20])=[CH:9][C:8]=1[CH3:31])[C:4]([OH:35])=[O:3])[CH3:34]
Reactant: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccccc3C(F)(F)F)oc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCc2nc(-c3ccccc3C(F)(F)F)oc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], [rac]-2-ethoxy-3-{2-methyl-4-[5-methyl-2-(2-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionic acid ethyl ester was treated with LiOH to obtain [rac]-2-ethoxy-3-{2-methyl-4-[5-methyl-2-(2-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionic acid as colorless liquid, which can be separated into its antipodes by methods known in the art, such as separation of the antipodes via diastereomeric salts by crystallization with optically pure amines such as e.g. (R) or (S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbens or a chiral eluent to give the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12](=[O:14])(=[O:13])[C:11]3[CH:15]=[C:16]([C:19](O)=[O:20])[CH:17]=[CH:18][C:10]=3[CH2:9][CH2:8][C:7]=2[CH:22]=1.C1C2C=CC3C=CC=CC=3S(=O)(=O)C=2C=C(C(O)=O)C=1>>[OH:20][CH2:19][C:16]1[CH:17]=[CH:18][C:10]2[CH2:9][CH2:8][C:7]3[CH:22]=[C:3]([CH2:2][OH:1])[CH:4]=[CH:5][C:6]=3[S:12](=[O:14])(=[O:13])[C:11]=2[CH:15]=1
Reactant: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccc(CO)cc1CC2
Agent: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1C=C2
Product: O=S1(=O)c2ccc(CO)cc2CCc2ccc(CO)cc21

Procedure:
Repeat the process of Example 6, substituting an equivalent quantity of 8-hydroxymethyl-10,11-dihydrodibenzo[b,f]thiepin-3-carboxylic acid 5,5-dioxide for the dibenzo[b,f]thiepin-3-carboxylic acid 5,5-dioxide, to obtain the title product.
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]([O:7][CH3:8])=[O:6].[N:9]([C@H:12]1[C@@H:15]([CH2:16][OH:17])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:13]1=[O:26])=[N+:10]=[N-:11]>CN(C)C=O>[N:9]([C@H:12]1[C@@H:15]([CH2:16][O:17][CH2:4][C:5]([O:7][CH3:8])=[O:6])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:13]1=[O:26])=[N+:10]=[N-:11]
Reactant: COC(=O)CBr
Reactant: COc1ccc(N2C(=O)[C@@H](N=[N+]=[N-])[C@H]2CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COC[C@@H]1[C@H](N=[N+]=[N-])C(=O)N1c1ccc(OC)cc1
Temperature: -20 °C

Procedure:
A suspension of 60% sodium hydride (749 mg, 18.72 mmole) was washed under argon with hexane (9 ml). The sodium hydride was then cooled to -20° C. and dimethylformamide (20 ml) was added. The mixture was then cooled to -50° C. and methyl bromoacetate (1.77 ml, 18.72 mmole) was added via syringe. Next, a solution of (±)-(cis)-3-azido-4-hydroxymethyl-1-(4-methoxyphenyl)-2-oxoazetidine (3.303 g, 13.37 mmole) in dimethylformamide (25 ml) was added dropwise. The reaction was stirred at -50° C. for ten minutes, warmed to -20° C. over 40 minutes, stirred at this temperature for thirty minutes, and then stirred at -5° C. overnight (ca. sixteen hours). The solvent was mostly removed in vacuo (30° C.). The residue was treated with ether, then pH 4.5 monobasic potassium phosphate buffer. The aqueous layer was extracted with additional ether. The organic extracts were washed with cold 0.5 N hydrochloric acid, water, brine, dried (sodium sulfate), and filtered and concentrated to 4.2 g of an orange oil. The crude product was chromatographed on silica gel (180 g, 230-400 mesh) eluting with 60% hexane-ethyl acetate. Combination of fractions 35-46 (20 ml fractions), concentration and drying in vacuo produced 2.46 g of the title compond as an oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]2[N:9]([CH3:21])[N:10]=[C:11]([C:12]3[CH:17]=[C:16]([F:18])[C:15]([OH:19])=[C:14]([Br:20])[CH:13]=3)[C:6]2=[CH:5][N:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][OH:31]>CN(C=O)C.CO>[NH2:2][C:3]1[N:8]=[C:7]2[N:9]([CH3:21])[N:10]=[C:11]([C:12]3[CH:17]=[C:16]([F:18])[C:15]([O:19][CH2:29][CH2:30][OH:31])=[C:14]([Br:20])[CH:13]=3)[C:6]2=[CH:5][N:4]=1
Reactant: Cn1nc(-c2cc(F)c(O)c(Br)c2)c2cnc(N)nc21
Reactant: OCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1nc(-c2cc(F)c(OCCO)c(Br)c2)c2cnc(N)nc21
Temperature: 120 °C

Procedure:
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-bromo-6-fluoro-phenol hydrochloride (Example 42b) (30 mg, 0.08 mmol) is dissolved in DMF (1 ml) then treated with K2CO3 (24 mg, 0.18 mmol) and 2-bromoethanol (5.7 μL, 0.08 mmol). The reaction mixture is heated at 120° C. for 3 hours then cooled to room temperature, diluted with MeOH and concentrated onto silica. Purification by flash column chromatography on silica using iso-hexanes:EtOAc (50% EtOAc to 100% EtOAc) followed by recrystallisation from MeOH afforded the title compound as an off-white solid.
Reaction SMILES: [CH3:1][C:2]([OH:13])([CH3:12])[CH2:3][N:4]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[N:5]1.[H][H]>CO.[Pd]>[NH2:9][C:7]1[CH:6]=[N:5][N:4]([CH2:3][C:2]([CH3:12])([OH:13])[CH3:1])[CH:8]=1
Reactant: [H][H]
Reactant: CC(C)(O)Cn1cc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Product: CC(C)(O)Cn1cc(N)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
2-methyl-1-(4-nitro-1H-pyrazol-1-yl)propan-2-ol (2.0 g, 10.8 mmol) was dissolved in MeOH (50 mL) and 10% Pd/C (240 mg) was added. A hydrogen balloon was fitted over the reaction and the reaction was allowed to stir at rt for 16 hrs. The reaction was checked using the polar APCI method and LCMS showed 70% complete with 30% starting material remaining. Another 200 mg of 10% Pd/C was added and the balloon was re-charged with fresh hydrogen. After 4 hrs, the reaction was complete. The reaction was filtered through Celite, washing with MeOH (three×50 mL) and the combined filtrate was concentrated to dryness. Purification was accomplished via flash chromatography eluting with gradient of 3%-20% MeOH in DCM. The pure fractions were pooled and concentrated to afford the title compound (1.4 g, 84% yield) as a purple solid. 1H NMR (400 MHz, chloroform-d) δ ppm 1.14 (s, 6H), 3.92 (s, 2H), 7.04 (s, 1H), 7.19 (s, 1H); m/z (APCI+) for C7H13N3O 156.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:40]=[CH:39][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C@@H:16]3[CH2:21][N:20]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[CH2:19][CH2:18][N:17]3C(OC(C)(C)C)=O)=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1>Cl>[F:1][C:2]1[CH:40]=[CH:39][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C@H:16]3[NH:17][CH2:18][CH2:19][N:20]([C:22]([O:24][CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[O:23])[CH2:21]3)=[O:15])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
Step (b) A flask was charged with (S)-4-benzyl 1-tert-butyl 2-(4-(4-fluorophenoxy)phenylcarbamoyl)piperazine-1,4-dicarboxylate (1.46 g, 2.75 mmol) and hydrogen chloride (4N in dioxane, 10 mL). The mixture was stirred at ambient temperature for 1 hour and then quenched with saturated sodium bicarbonate (aq., 40 mL). The mixture was extracted with ethyl acetate (30 mL) and the extract was washed with deionized water (10 mL) and then brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give crude (S)-benzyl 3-(4-(4-fluorophenoxy)phenylcarbamoyl)piperazine-1-carboxylate (1.08 g, 2.41 mmol), which was carried forward without further purification.
Reaction SMILES: [C:1]([CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1C(OC(C)(C)C)=O)#[N:2].[ClH:16]>CO>[ClH:16].[NH:5]1[CH2:6][CH2:7][CH2:8][C@H:4]1[CH2:3][C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CC#N
Agent: Cl
Solvent: CO
Product: N#CC[C@@H]1CCCN1
Temperature: 40 °C

Procedure:
A solution of tert-butyl (S)-2-cyanomethylpyrrolidine-1-carboxylate (Intermediate 139, 13.0 g) in methanol (130 mL) and concentrated hydrochloric acid (13 mL) was stirred and heated at 40° C. overnight. After cooling, the mixture was concentrated under vacuum and the residue was diluted with toluene and reconcentrated. Ethanol (20 mL) was added and the resultant solid was collected by filtration and washed with hexane to give ((S)-pyrrolidin-2-yl)acetonitrile hydrochloride (8.0 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:13]C)[CH:5]=[C:6]2[C:10]=1[C:9]([CH3:12])([CH3:11])[CH2:8][CH2:7]2.C(S)CCCCCCCCCCC.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[C:6]2[C:10]=1[C:9]([CH3:11])([CH3:12])[CH2:8][CH2:7]2
Reactant: COc1cc(F)c2c(c1)CCC2(C)C
Agent: CCCCCCCCCCCCS
Agent: Cl
Agent: [Al+3]
Solvent: Cc1ccccc1
Product: CC1(C)CCc2cc(O)cc(F)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a solution of 7-fluoro-5-methoxy-1,1-dimethyl-2,3-dihydro-1H-indene (4.76 g, 24.51 mmol) and 1-dodecanethiol (17.71 mL, 73.52 mmol) in toluene (50 mL) was added aluminium chloride (9.80 g, 73.52 mmol) at 0° C., and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent; ethyl acetate/hexane) to give 7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-ol (4.17 g, 23.14 mmol, 94%) as an off-white solid.