Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C@@H:10]2[NH:15][CH2:14][CH2:13][N:12]([C:16]3[C:17]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:18]=4[NH:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)[CH2:11]2)[CH:5]=[CH:6][CH:7]=1.C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C@@H:10]2[N:15]([CH3:34])[CH2:14][CH2:13][N:12]([C:16]3[C:17]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:18]=4[NH:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)[CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc2c(c1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2cccc(F)c2)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1ccc2c(c1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCc2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91.9 %

Procedure:
Combine 11-{(S)-3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-3-methyl-5H-dibenzo[b,e][1,4]diazepine (385.5 mg, 0.93 mmol), formaldehyde (83.0 μL, 1.02 mmol, 37% in water), and 1,2-dichloroethane (30.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (295.6 mg, 1.39 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion and wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (90:10) to give 366.2 mg (92%) of the title compound as a yellow foam: mp 63°, dec; mass spectrum (ion spray): m/z=429.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7](O)[CH2:6][CH2:5]2.S(Cl)([Cl:14])=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([Cl:14])[CH2:6][CH2:5]2
Reactant: OC1CCc2cc(Br)ccc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClC1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.1 (2.0 g) in DCM (10 mL) in an ice-bath, was treated with thionyl chloride (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into ice water and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and concentrated under vacuum. The resulting material was chromatographed on a silica gel column, eluting with 5-10% EtOAc in hexane, to afford 1.2. 1H NMR (DMSO-d6) δ 7.54 (s, 1H), 7.45 (dd, 1H, J1=1.0 Hz, J2=8.50 Hz), 7.37 (d, 1H, J=8.0 Hz), 3.07 (m, 1H), 5.60 (q, 1H), 2.93 (m, 1H), 2.59 (m, 1H), 2.26 (m, 1H).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].FC(F)(F)C([N:11]=[S:12]([C:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[CH:20][CH:21]=2)[N:16]([C:31]2[N:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[F:43])=[CH:33][N:32]=2)[C:15]=1C)[O-:13])=O>C(#N)C.CO>[F:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[C:34]1[CH:33]=[N:32][C:31]([N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[C:19]([C:23]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[O:24])[CH:18]=3)[C:14]([S:12]([CH3:1])(=[NH:11])=[O:13])=[CH:15]2)=[N:36][CH:35]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(S([O-])=NC(=O)C(F)(F)F)c2ccc(C(=O)N3CCOCC3)cc2n1-c1ncc(-c2ccccc2F)cn1
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: CS(=N)(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Reaction time: 1 h

Procedure:
Potassium carbonate (0.143 g, 1.04 mmol) was added at room temperature to a stirred suspension of 287a) (0.3 g, 0.52 mmol) in acetonitrile/methanol (1:1, 9.6 mL) and the mixture was stirred for 1 h. The solvents were evaporated and the residue was purified by column chromatography [alumina; dichloromethane with 1% methanol] and washed with ether. Pink solid. Yield: 0.12 g (48% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=2)[N:7]=1
Reactant: Nc1cn2nc(Cl)ccc2n1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cn2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.6 %

Procedure:
To a 250-mL, round-bottomed flask was added 6-chloroimidazo[1,2-b]pyridazin-2-amine from Step 3 (0.67 g, 4.0 mmol), CH2Cl2 (60 mL), acetic anhydride (0.45 mL, 4.8 mmol), pyridine (0.49 mL, 6.0 mmol), and 4-(dimethylamino)pyridine (4.9 mg, 0.040 mmol). The mixture was stirred at 25° C. for 24 h. The reaction mixture was concentrated and then diluted with aq. NaHCO3 and extracted with 25% iPrOH/CHCl3 (3×100 mL). The combined extracts were washed with brine (100 mL), dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (0 to 4% MeOH (2 M in NH3)/CH2Cl2) afforded the title compound as a yellow solid (0.62 g, 74%). MS (ESI positive ion) m/z: 211 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.10 (s, 3H), 7.33 (d, J=9.4 Hz, 1H), 8.06 (d, J=9.4 Hz, 1H), 8.26 (s, 1H), 10.95 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[S:8]([N:11]([CH3:26])[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[CH:17]2)(=[O:10])=[O:9].C(N(CC)CC)C.[C:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])[CH3:35]>O1CCCC1>[C:34]([N:37]1[CH2:42][CH2:41][N:40]([CH2:2][C:3]2[S:4][CH:5]=[CH:6][C:7]=2[S:8]([N:11]([CH3:26])[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:20]=2[NH:19][C:18]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[CH:17]3)(=[O:10])=[O:9])[CH2:39][CH2:38]1)(=[O:36])[CH3:35]
Reactant: CC(=O)N1CCNCC1
Reactant: CN(c1cccc2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1ccsc1CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCN(Cc2sccc2S(=O)(=O)N(C)c2cccc3cc(-c4nccs4)[nH]c23)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 81.3 %

Procedure:
To a solution of 2-(chloromethyl)-N-methyl-N-[2-(1,3-thiazol-2-yl)-1H-indol-7-yl]thiophene-3-sulfonamide (110 mg) and triethylamine (150 μL) in tetrahydrofuran (5 mL) was added N-acetylpiperazine (33 mg). The reaction mixture was stirred at room temperature for 10 hr. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound (108 mg, yield 81%) as pale-yellow crystals. melting point 242° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=1[NH2:8].[C:11](O)(=O)[CH3:12]>>[CH3:11][C:12]1[NH:1][C:2]2[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=2[N:8]=1
Reactant: CC(=O)O
Reactant: Cc1cc(O)cc(N)c1N
Product: Cc1nc2c(C)cc(O)cc2[nH]1

Procedure:
0.553 g (4.00 mml) 3,4-diamino-5-methyl-phenol in 5.00 mL glacial acetic acid were boiled for 3 h. Then the reaction mixture was evaporated down and dried under HV.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=2)[CH:3]=1.C(N(CC)C(C)C)(C)C.[C:31]([C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]>CN(C)C(=O)C>[C:31]([C:35]1[CH:36]=[CH:37][C:38]([C:39]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[CH:5]=[C:4]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=3)[CH:3]=2)=[O:40])=[CH:42][CH:43]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CNc1nccc(-c2cc(N)c3cc(OC)ccc3c2)n1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nccc(-c2cc(NC(=O)c3ccc(C(C)(C)C)cc3)c3cc(OC)ccc3c2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(4-amino-6-methoxy-2-naphthyl)-N-methylpyrimidin-2-amine (33) (252 mg, 0.900 mmol), N,N-dimethylacetamide (4 mL) was treated with N,N-diisopropylethylamine (0.9 mL, 5.2 mmol) followed by 4-(tert-butyl)benzoyl chloride (181 mg, 0.9 mmol) and stirred for 16 hours at room temperature. The mixture was partitioned between ethyl acetate (150 mL) and water (120 mL). The aqueous layer was removed and the organic layer was washed with water (2×100 mL), dried over anhydrous sodium sulfate, filtered, concentrated (rotary) and dried under high vacuum to afford the crude desired product, which was purified by reverse phase chromatography on preparative LC/UV/MS system using a mass triggered fractionation. Compound was eluted from the HPLC column (Maccel 120-10-C18 SH 10 μm 20 mmID×50 mm) at 88 mL/min with acetonitrile/water gradient using 0.1% FA as a modifier. 4-tert-butyl-N-{7-methoxy-3-[2-(methylamino)pyrimidin-4-yl]-1-naphthyl}benzamide (184) was isolated as an off-white solid (95 mg). M.p.=231-232° C.; 400 MHz 1H NMR (DMSO-d6) δ: 10.39 (s, 1H), 8.59 (s, 1H), 8.34-8.39 (m, 2H), 8.06 (m, 3H), 7.61 (d, J=6.7 Hz, 2H), 7.31 (m, 3H), 7.16 (s, 1H), 3.87 (s, 3H), 3.34 (br s, 3H), 1.36 (s, 9H); Experimental Elemental Analysis (0.23 equivalents of formic acid)=72.52% C, 6.15% H, 12.21% N; Calculated Elemental Analysis 72.50% C, 6.36% H, 12.42% N; LCMS (m/z): 442 [M+H].
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:48][CH2:47][CH2:46][CH2:45][N:44]([CH2:49][CH2:50][C:51]([O:53][CH3:54])=[O:52])[C:43]1=[O:55]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:41][C@H:42]1[CH2:48][CH2:47][CH2:46][CH2:45][N:44]([CH2:49][CH2:50][C:51]([O:53][CH3:54])=[O:52])[C:43]1=[O:55])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: COC(=O)CCN1CCCC[C@H](N)C1=O
Product: COC(=O)CCN1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)N[C@H]2CCS[C@H]3CCC[C@@H](C(=O)OC)N3C2=O)Cc2ccccc2)C1=O

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((S)-1-(3-methoxy-3-oxopropyl)-2-oxoazepan-3-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (5.0 mg, 0.0088 mmol) and Intermediate 27 (4.4 mg, 0.018 mmol) to give a white solid (2.1 mg, 29% yield). Anal. Calcd. for C41H54N4O8S m/z 762.5. found: 763.5 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.26-7.06 (m, 10H), 5.50 (d, J=3.3 Hz, 1H), 5.15 (d, J=6.6 Hz, 1H), 4.98 (dd, J=8.8, 4.4 Hz, 1H), 4.44 (d, J=11.0 Hz, 1H), 3.67-3.62 (m, 6H), 3.62-3.48 (m, 2H), 3.36 (dd, J=15.4, 4.4 Hz, 1H), 3.12 (d, J=9.3 Hz, 1H), 2.89-2.72 (m, 3H), 2.72-2.59 (m, 4H), 2.59-2.50 (m, 2H), 2.36 (d, J=12.1 Hz, 1H), 2.06 (d, J=7.1 Hz, 1H), 1.97 (d, J=11.5 Hz, 1H), 1.87 (d, J=12.1 Hz, 1H), 1.84-1.54 (m, 10H), 1.54-1.40 (m, 2H), 1.39-1.27 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20]Br.Cl>CN(C=O)C.CCOC(C)=O>[CH2:12]([O:11][C:9]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:10])[CH3:13]
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Reactant: BrCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(c2ccc(Br)cc2)CCCC1
Reaction time: 0.17 h

Procedure:
To a solution of ethyl 4-bromophenylacetate (2 g, 8.2 mmol) in DMF (20 mL) at 0° C. was added sodium hydride (60% in mineral oil; 0.72 g, 18.1 mmol), and the mixture was stirred for 10 minutes. 1,4-Dibromobutane (1.07 mL, 9.0 mmol) was added, and the reaction was stirred at room temperature for 30 minutes. Once no starting material was seen by analytical tlc, the mixture was worked up with EtOAc and aqueous 10% HCl, and the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:12]([OH:15])(=[O:14])=[O:13])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[K].Cl.[CH3:18]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:12]([OH:15])(=[O:13])=[O:14])[C:10]=1[OH:11])[C:5]([O:7][CH3:18])=[O:6]
Reactant: CO
Reactant: O=C(O)c1cc(O)c(O)c(S(=O)(=O)O)c1
Agent: Cl
Agent: [K]
Product: COC(=O)c1cc(O)c(O)c(S(=O)(=O)O)c1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
3,4-Dihydroxy-5-sulfobenzoic acid, monopotassium salt (10.0 g, 36.7 mmoles) was slurried in 300 ml of dry methanol, cooled to 0° C., and treated for five minutes with dry hydrogen chloride. The resulting solution was allowed to warm to room temperature and was stirred for 48 hours. The mixture was filtered and the volatile materials were removed in vacuo. The resulting solid was dried in vacuo at 60° C. to give the title compound, 8.51 g, m.p. 116° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:16][C:17]1[C:18]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:19]=2[S:20][CH:21]=1>>[F:26][C:24]1[CH:23]=[CH:22][C:19]2[S:20][CH:21]=[C:17]([CH2:16][N:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:14]=[C:6]3[C:4]([OH:3])=[O:5])[C:18]=2[CH:25]=1
Reactant: Fc1ccc2scc(CBr)c2c1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Product: O=C(O)c1cc2ccccc2n1Cc1csc2ccc(F)cc12

Procedure:
Using general procedure B, 1H-indole-2-carboxylic acid ethyl ester was coupled with 3-bromomethyl-5-fluoro-benzo[b]thiophene (Lit. 18) and the product obtained was hydrolyzed to give the title compound as pale yellow solid. MS: 324.0 ([M−H]−).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([OH:25])[CH:12]=[CH:13][C:14]2=[O:24])[CH2:6]1)(=[O:3])[CH3:2].Cl[CH2:27][O:28][CH2:29][CH3:30].C(N(C(C)C)CC)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([O:25][CH2:27][O:28][CH2:29][CH3:30])[CH:12]=[CH:13][C:14]2=[O:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)C=C[C@]32O)C1
Reactant: CCOCCl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOCO[C@]12C=CC(=O)[C@@]1(C)CC[C@H]1[C@H]2CC=C2C[C@@H](OC(C)=O)CC[C@@]21C

Procedure:
A solution of 9.20 g of 3β-acetoxy-14β-hydroxyandrosta-5,15-dien-17-one (G. Groszek et al., Bull. Pol. Acad. Sci., Chem., 34, 1986, 313), 11 ml of ethyl chloromethyl ether, 54 ml of diisopropylethylamine in 750 ml of dichloromethane was heated at reflux for 24 hrs. The solution was then cooled and poured into 500 ml of aq. 8% citric acid solution. The lower layer was separated, washed with water, dried over sodium sulfate and avaporated to dryness. The crude product was purified by chromatography using cyclohexane/chloroform/acetone 80/10/10 as eluant to give 6.10 g of 3β-acetoxy-14β-ethoxymethoxyandrosta-5,15-dien-17-one as a white solid.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C1C=CC=CN=1)C.[CH3:29][Si:30]([CH3:35])([CH3:34])[CH2:31][CH2:32]O.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:17]([O:19][CH2:32][CH2:31][Si:30]([CH3:35])([CH3:34])[CH3:29])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)CCO
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)OCC[Si](C)(C)C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
A mixture of 20.1 g (75.7 mmol) of [(phenylmethoxy)carbonyl]-L-leucine, 0.925 g (7.57 mmol) of dimethylaminopyridine and 8.95 g (75.7 mmol) of 2-trimethylsilylethanol in 200 ml of dichloromethane was cooled in an ice bath under nitrogen and treated with a solution of 15.6 g (75.7 mmol) of dicyclohexylcarbodiimide in 50 ml of dichloromethane. The ice bath was removed after 30 minutes and the reaction allowed to come to room temperature overnight. The reaction mixture was filtered, concentrated in vacuo and partitioned between 800 ml of ether and 200 ml of water. The organic layer was separated and further rinsed with saturated sodium bicarbonate, water, 10% potassium bisulfate, water and brine, then dried (magnesium sulfate) and concentrated in vacuo to 26.1 g of crude product. Flash filtration over silica gel (180 g in 20:1, hexanes:ethyl acetate) yielded 22.9 g of crude product which was chromatographed using a Waters Prep 500 LC, two columns eluted with 15:1, hexanes:ethyl acetate (250 ml/minute, 200 ml fractions). Combining the pure fractions yielded 19.6 g of the title compound as an oil: [α]D =7.3° (c=1, chloroform).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9].[OH-].[Na+]>>[C:1]([NH:5][CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: C[Si](C)(C)CCl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)NC[Si](C)(C)C
Temperature: 200 °C

Procedure:
A mixture of tert-butylamine (18.0 mL, 171 mmol) and (chloromethyl)trimethylsilane (7.00 g, 57.1 mmol) was heated in a thick-walled glass tube at 200° C. overnight. After cooling to ambient temperature, the reaction mixture was poured into 1 N NaOH and extracted three times with diethyl ether. The combined organic extracts were washed with brine, dried (MgSO4), and the volatiles evaporated in vacuo. Distillation (atmospheric pressure; ˜135° C.) of the residual liquid gave the title compound as a colorless liquid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:9]2=[N:10][CH:11]=1)=[O:5])C.[OH-].[Na+]>>[F:32][C:26]1[CH:27]=[C:28]([I:31])[CH:29]=[CH:30][C:25]=1[NH:24][C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=[C:9]2[N:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[N:13]=[CH:14][C:8]=12
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccc(OC)cc2)c1Nc1ccc(I)cc1F
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(Cn2ncc3c(Nc4ccc(I)cc4F)c(C(=O)O)cnc32)cc1
Temperature: 65 °C
Yield: 97.8 %

Procedure:
To a suspension of 4-(2-fluoro-4-iodophenylamino)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (380 mg, 0.71 mmol) in IMS (10 mL) was added aqueous sodium hydroxide solution (1.78 mL, 1M, 1.78 mmol). The reaction mixture was heated at 65° C. for 2 hours, during which time all solids dissolved. Volatile solvents were removed in vacuo and the resultant solution was acidified to pH ˜3 by careful addition of aqueous hydrochloric acid (1M) causing a precipitate to form. The precipitate was collected by filtration and dried under vacuum at 45° C. to yield the title compound as a brown solid (360 mg, 100%). LCMS (Method B): RT=3.84 min, [M+H]+=519.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Br.C([O-])([O-])=O.[K+].[K+].[CH3:17][O:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([N:26]2[C:31](=[O:32])[N:30](CC3C(F)=CC(F)=CC=3F)[C:29]3[CH:43]=[CH:44][CH:45]=[CH:46][C:28]=3[S:27]2(=[O:48])=[O:47])=[CH:21][C:20]=1[CH3:49]>O1CCOCC1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][N:30]1[C:29]2[CH:43]=[CH:44][CH:45]=[CH:46][C:28]=2[S:27](=[O:48])(=[O:47])[N:26]([C:22]2[CH:23]=[C:24]([CH3:25])[C:19]([O:18][CH3:17])=[C:20]([CH3:49])[CH:21]=2)[C:31]1=[O:32]
Reactant: COc1c(C)cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc1C
Reactant: Fc1cccc(Cl)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1c(C)cc(N2C(=O)N(Cc3c(F)cccc3Cl)c3ccccc3S2(=O)=O)cc1C

Procedure:
The title compound (0.20 g, 0.42 mmol) was prepared from (IntA6) (0.35 g, 1.00 mmol), 2-chloro-6-fluorobenzyl bromide (0.34 g, 1.5 mmol) and K2CO3 (0.20 g, 1.5 mmol) in 1,4-Dioxane (10 mL) using the methods of (115).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].CON(C)[C:11]([CH:13]1[CH2:17][S:16][C:15](=[O:18])[N:14]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:12].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:14]2[C@H:13]([C:11](=[O:12])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])[CH2:17][S:16][C:15]2=[O:18])=[CH:25][CH:24]=1
Reactant: COc1ccc(CN2C(=O)SCC2C(=O)N(C)OC)cc1
Reactant: COP(C)(=O)OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2C(=O)SC[C@H]2C(=O)CP(=O)(OC)OC)cc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
A dry three-necked round bottom flask fitted with an internal temperature probe and a mechanical stirrer was charged with dimethyl methylphosphonate (36.7 mL, 0.338 mol) and 0.5 L of THF. The solution was purged with nitrogen and cooled to −70° C. 126 mL of a 2.55 M solution of n-butyllithium was added dropwise maintaining an internal reaction temperature less than −60° C. In a separate flask, 3-(4-methoxy-benzyl)-2-oxo-thiazolidine-4-carboxylic acid methoxy-methyl-amide (50.0 g, 0.161 mol) was dissolved in 300 mL of dry THF. The resulting solution was added to the solution of dimethyl methylphosphonate anion at a rate maintaining an internal reaction temperature less than −60° C. The reaction was monitored by HPLC and was considered complete upon the disappearance of starting material. The reaction mixture was slowly added to 50 mL of a 10% citric acid solution at a rate that maintained a temperature of less than 5° C. The mixture was diluted with 0.35 L of water. The THF was removed by distillation at atmospheric pressure. The product was extracted with 300 mL of ethyl acetate. The organic phase was separated and a suspension was formed by the addition of 250 mL of n-heptane. The suspension was stirred for 30 minutes. The resulting solid was isolated by filtration and was dried in a vacuum oven at 40° C. for 12 hours. Approximately 57 g of (R)-dimethyl 2-(3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-2-oxoethylphosphonate was obtained (94% yield). 1H NMR (300 MHz, DMSO) δ 7.16 (d, 8.5 Hz, 2H), 6.89 (d, 8.5 Hz, 2H), 4.78 (d, J=15.2 Hz, 1H), 4.69-4.61 (m, 1H), 3.79-3.55 (m, 11H), 3.51-3.27 (m, 3H). 13C NMR (75 MHz, DMSO) δ 36.3, 38.0, 46.9, 53.5, 55.08, 66.1, 114.7, 129.0, 129.9, 159.4, 171.9, 199.0; [α]25.0D-29.60 (c=1.00, EtOH).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]1(=O)[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]1>C(O)C>[OH:13][C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:8][CH:9]=1
Reactant: C1CCNCC1
Reactant: O=C1CCC(=O)CC1
Solvent: CCO
Product: Oc1ccc(N2CCCCC2)cc1
Yield: 53.7 %

Procedure:
0.85 g of piperidine and 2.24 g of 1,4-cyclohexanedione were heated with stirring in 15 ml of ethanol at 50 to 60° C. and reacted in air for 8 hours. During the reaction, ethanol was added as needed. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure and the resultant was separated by silica gel column chromatography (n-hexane:ethyl acetate=2:1) and 0.95 g of 1-(4-hydroxyphenyl)piperidine was obtained (yield 53.7%).