Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O>[CH2:16]([O:15][C:13]([CH2:12][N:4]([CH:1]([CH3:3])[CH3:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)CBr
Reactant: CC(C)Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(c1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
N-isopropyl aniline 1.0 g, ethyl bromoacetate 2.47 g, potassium carbonate 5.11 g and sodium iodide 5.55 g were dissolved in N,N-dimethylformamide 14 ml in a nitrogen atmosphere and stirred under reflux with heating. After 1 hour, the reaction mixture was cooled to room temperature and then partitioned by adding water and diethyl ether, and the organic layer was washed with water and then with brine, dried over magnesium sulfate anhydride, and evaporated. The residue was purified by silica gel column chromatography (hexane/diethyl ethersystem) to give N-ethoxycarbonylmethyl-N-isopropyl aniline 1.62 g. A part 550 mg of this product was dissolved in tetrahydrofuran 10 ml, and 1M lithium aluminum hydride in tetrahydrofuran 2.5 ml was added thereto under cooling in an ice bath in a nitrogen atmosphere. The mixture was stirred in the ice bath for 40 minutes, and water 0.1 ml, 2N aqueous sodium hydroxide 0.1 ml, water 0.3 ml, and diethyl ether 5 ml were added in this order and stirred. The insolubles were filtered off through Celite, and the filtrate was evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system), whereby the title compound 383 mg, 86% was obtained as a colorless oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]([C:18]([CH:20]1[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])[CH:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)=[O:4].[CH3:33][N:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)[NH2:35].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+].[OH-].[Li+].C(O)(C(F)(F)F)=O>ClCCCl.[Cl-].[Na+].O.O.CO>[CH3:30][C:29]([CH3:32])([CH3:31])[C:28]#[C:27][C:7]1[S:6][C:5]([C:3]([OH:2])=[O:4])=[C:9]([N:10]([C:18]([CH:20]2[CH2:21][CH2:22][CH:23]([CH3:26])[CH2:24][CH2:25]2)=[O:19])[CH:11]2[CH2:12][CH2:13][CH:14]([NH:35][N:34]([CH3:33])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[CH2:15][CH2:16]2)[CH:8]=1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CCC(C)CC1)C1CCC(=O)CC1
Reactant: CN(N)c1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CO
Solvent: O
Solvent: ClCCCl
Product: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C2CCC(NN(C)c3ccccn3)CC2)CC1
Reaction time: 0.5 h
Yield: 38.1 %

Procedure:
A mixture of 5-(3,3-Dimethyl-but-1-ynyl)-3-[(4-methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (412 mg, 0.90 mmol) and N-Methyl-N-pyridin-2-yl-hydrazine (222 mg, 1.8 mmol) in DCE (6 mL) was treated with AcOH (200 μL, 3.0 mmol) followed by NaBH(OAc)3 (300 mg, 4.08 mmol) in two or three portions. After 30 min, NaHCO3 (saturated aqueous solution, 4-8 mL) was added to the mixture, followed by brine (20 mL), and the crude product was extracted with ethyl acetate (2×20 mL). The combined organic layers were concentrated and the crude material was dissolved in a 3:2:1 mixture of THF:MeOH:water (20 mL), treated with lithium hydroxide (4.5 mmol, 188 mg) and heated to 60 deg C. for 2 hours. The residue was purified by HPLC (Gemini column, 35% acetonitrile:water, 2 min, 35-50% acetonitrile:water, 2 min, 50-100% acetonitrile: water 13 min, both solvents containing 0.1% trifluoroacetic acid). This resulted in 189 mg (37% yield) of the title compound as its trans isomer (TFA salt): MS (m/z): 551.3 [M−H]+; HPLC retention time: 3.39 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid) and 71 mg (14% yield) of the title compound as its cis isomer (TFA salt): MS (m/z): 551.3 [M−H]+; HPLC retention time: 3.52 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12].[N:24]1[C:29]2[NH:30][CH:31]=[CH:32][C:28]=2[CH:27]=[N:26][CH:25]=1.[OH-].[K+].O>CO>[F:1][C:2]1[C:7]([CH:8]([OH:9])[C:32]2[C:28]3[CH:27]=[N:26][CH:25]=[N:24][C:29]=3[NH:30][CH:31]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: O=Cc1cccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1F
Reactant: c1ncc2cc[nH]c2n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=S(=O)(Nc1cccc(C(O)c2c[nH]c3ncncc23)c1F)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 43.3 %

Procedure:
To N-(2-fluoro-3-formyl-phenyl)-4-trifluoromethyl-benzenesulfonamide (34, 172 mg, 0.50 mmol) in 1 mL of methanol, 7H-pyrrolo[2,3-d]pyrimidine (6, 71 mg, 0.60 mmol) and potassium hydroxide (84 mg, 1.5 mmol) were added under an atmosphere of nitrogen. The reaction was stirred at room temperature for 24 hours, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum and the residue was purified by silica gel column chromatography eluting with 5% methanol in dichloromethane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a solid (P-0034, 101 mg, 44%). MS(ESI) [M+H+]−=467.8.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][CH:11]=[O:12])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:13]([Mg]Br)[CH2:14][CH:15]([CH3:17])[CH3:16].C(Br)CC(C)C.[Mg].[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH2:10][CH:11]([OH:12])[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Reactant: CC(C)CC[Mg]Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CC(C)CCBr
Solvent: C1CCOC1
Product: CC(C)CCC(O)CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N-t-butoxycarbonylsarcosinal (3.46 g) in dry tetrahydrofuran (100 ml) which was cooled to -78° C., was added dropwise a solution of isopentylmagnesium bromide prepared from isopentyl bromide (30.8 g) and magnesium (4.86 g) in dry tetrahydrofuran (200 ml). After the addition was complete, the reaction mixture was allowed to warm to ambient temperature and stirred at the same temperature for 4 hours. After saturated aqueous ammonium chloride (200 ml) was added thereto, the resulting mixture was extracted with diethyl ether (300 ml×2). The combined extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified with silicagel column chromatography (20% ethyl acetate in n-hexane as eluent) to give 1-(N-t-butoxycarbonyl-N-methylamino)-2-hydroxy-5-methylhexane (3.96 g).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O.[N+]([O-])(O)=O.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH2:28])=[NH:27])=[CH:21][C:20]=1[N+:29]([O-:31])=[O:30].[OH-].[Na+]>C(O)(C)C>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]2[N:28]=[C:5]([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)[CH:4]=[CH:3][N:27]=2)=[CH:21][C:20]=1[N+:29]([O-:31])=[O:30]
Reactant: Cc1ccc(NC(=N)N)cc1[N+](=O)[O-]
Reactant: CN(C)C=CC(=O)c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O=[N+]([O-])O
Product: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 104130488 %

Procedure:
3-Dimethylamino-1-(3-pyridyl)-2-propen-1-one (20 g, 0.1 μmol), 4-methyl-3-nitrophenyl-guanidine nitrate (32 g, 0.12 mol), and sodium hydroxide (6.8 g, 0.17 mol) were dissolved in isopropanol, and reacted under reflux for 28 hours. The reaction solution was cooled to 0° C., filtered, washed with isopropanol, water and ethanol, and dried to give N-(4-methyl-3-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine (32 g).
Reaction SMILES: [Mg].Cl[CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.CI.II.CON(C)[C:16]([CH:18]1[O:23][CH2:22][CH2:21][N:20]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:19]1)=[O:17].C(O)(=O)C.[NH4+].[Cl-].O>C1COCC1>[C:25]1([CH2:24][N:20]2[CH2:21][CH2:22][O:23][CH:18]([C:16]([CH:3]3[CH2:8][CH2:7][O:6][CH2:5][CH2:4]3)=[O:17])[CH2:19]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CON(C)C(=O)C1CN(Cc2ccccc2)CCO1
Reactant: ClC1CCOCC1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CI
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(C1CCOCC1)C1CN(Cc2ccccc2)CCO1
Temperature: 65 °C

Procedure:
An inerted 6 L reactor is charged with THF (242.5 mL), magnesium (54.47 g, 2240 mmol) and 5% of the total amount of 4-chlorotetrahydropyran (12.28 mL, 112 mmol). Then, a small amount of methyl iodide (0.5 mL) and one iodine crystal is added. The reaction mixture is stirred and heated up to 64-66° C. After initiation, the remaining 4-chlorotetrahydropyran (233.22 mL, 2127 mmol) diluted in THF (890 mL) is slowly added over 135 mins. The mixture is heated up for 30 additional minutes before being cooled to 0° C. Then, the Weinreb amide 2b (370 g, 1400 mmol) diluted in THF (2777 mL) is added over 180 mins between 0-4° C. and the mixture is stirred for a further 60 mins. Then, acetic acid (48 mL, 0.83 mmol) is added to the mixture followed by a 55/45:v/v:saturated NH4Cl/H2O mixture (2590 mL) keeping the temperature below 9° C. The organic layer is washed with a 60/40:v/v:saturated NH4Cl/H2O mixture (500 mL) and, after separation, toluene (1800 mL) and water (1800 mL) is added to the organic solution. Then after extraction, water (1100 mL) is added to the toluene mixture which is basified with 3.68 M Na2CO3aq (148 mL). The organic layer is dried over MgSO4, filtered and concentrated under reduced pressure to dryness to yield compound 8b as the free base (400.8 g, 98.6% yield).
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:25]1[N:26]=[CH:27][S:28][CH:29]=1)CCC>>[S:28]1[CH:29]=[C:25]([C:2]2[S:6][C:5]([N:7]3[CH2:11][C@:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:8]3=[O:19])=[CH:4][CH:3]=2)[N:26]=[CH:27]1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(-c2cscn2)s1

Procedure:
The title compound was prepared by a method analogous to that described in Example 5 from (R)-3′-(5-bromothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 4-(tri-n-butylstannyl)thiazole. The title compound (27 mg) was obtained as a pale solid, m/z 348 (MH+).
Reaction SMILES: COCC[N:5]1[C:9]([CH:10]([O:12][CH3:13])[CH3:11])=[C:8]([Cl:14])[N:7](Cl)[CH:6]1[C:16]1[C:21]([CH2:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:24][CH3:25].[Li]CCCC.CN([CH:34]=[O:35])C>C1COCC1>[CH2:24]([C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([CH2:22][CH3:23])[C:16]=1[C:6]1[N:7]([CH:34]=[O:35])[C:8]([Cl:14])=[C:9]([CH:10]([O:12][CH3:13])[CH3:11])[N:5]=1)[CH3:25]
Reactant: CN(C)C=O
Reactant: CCc1cccc(CC)c1C1N(Cl)C(Cl)=C(C(C)OC)N1CCOC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1-c1nc(C(C)OC)c(Cl)n1C=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of N-methoxyethyl 2-(2,6-diethylphenyl)-1-methoxyethyl-3,4-dichloroimidazole (3.27 g, 10 mmol.) in anhydrous THF is added n-BuLi (1.6M in hexane) (9.4 ml, 15 mmol) dropwise at −78° C. After the reaction mixture is stirred at −78° C. for 2 h, anhydrous DMF (3 equiv.) is added in one portion. The mixture is stirred at −78° C. for 30 min, then allowed to warm to room temperature slowly. The reaction mixture is quenched with water and extracted with ethyl acetate, dried over MgSO4, filtered, concentrated in vacuo and purified by chromatography on silica gel to give 2-(2,6-diethylphenyl)-1-methoxyethyl-4-chloro-imidazole-3-carboxaldehyde. This material is used to make various compounds of Formula I as depicted in Scheme 10 and further illustrated in Examples 4–9 and related examples.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[OH:15])[CH:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:3]=1.Br[CH2:25][CH:26]=[CH2:27]>>[CH2:27]([O:15][C:9]1[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:8]=1[C:6]1[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH:5]=1)[CH:26]=[CH2:25]
Reactant: Nc1nc(Nc2ccc(Cl)cc2)cc(-c2cc(Cl)ccc2O)n1
Reactant: C=CCBr
Product: C=CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(Cl)cc2)nc(N)n1
Yield: 80 %

Procedure:
Following the method described in Example 165, 2-[2-amino-6-(4-chloro-phenylamino)-pyrimidin-4-yl]-4-chloro-phenol and 3-bromo-propene provided the title compound (80% yield) 1H NMR (DMSO-d6) δ 4.68 (d, 2H, CH2), 5.25-5.28 (m, 1H, Ar), 5.36-5.41 (m, 1H, Ar), 6.03-6.08 (m, 1H, Ar), 6.36 (s, 2H, NH2), 6.70 (s, 1H, Ar), 7.14 (d, 1H, J=8.9 Hz, Ar), 7.31 (d, 2H, J=8.9 Hz, Ar), 7.40 (dd, 1H, J—2.8 Hz, J=8.8 Hz, Ar), 7.78 (d, 2H, J=8.9 Hz, Ar), 7.85 (d, 1H, J=2.8 Hz, Ar), 9.32 (s, 1H, NH).
Reaction SMILES: [CH2:1]([N:8]([C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C@@H:9]([CH3:13])[CH2:10][CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I>C1COCC1>[CH2:1]([N:8]([C@H:14]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:15])[C@H:9]([CH2:10][CH2:11][O:12][CH3:24])[CH3:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](CCO)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC[C@H](C)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81.3 %

Procedure:
(3S)-3-[Benzyl-[(1S)-1-phenylethyl]amino]butan-1-ol (17.54 g, 61.9 mmol) is dissolved in anhydrous THF (186 mL) and cooled to 0° C. under an argon atmosphere. Sodium hydride (4.95 g, 60% suspension in mineral oil, 123.8 mmol) is added portionwise over 10 min. The mixture is stirred at 0° C. for 15 min, and then allowed to warm to RT. Methyl iodide (10.54 g, 74.28 mmol) is added dropwise over 30 min. After stirring for 30 additional min, the reaction is quenched by the addition of a saturated solution of NH4Cl in water. The layers are separated and the aqueous layer is extracted with diethyl ether (2×100 mL). The combined organic layers are dried over MgSO4, concentrated, and the crude is purified by normal phase chromatography (two 120 g silica-gel cartridges, 10% of methyl tert-butyl ether in hexanes) to afford the title compound as a colorless oil (14.96 g, 81%). LC-ES/MS m/z 298 (M+1).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6]([C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)=[O:7].[OH-].[Na+]>CO.O>[Cl:3][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[CH:6]([C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)[OH:7]
Reactant: O=C(c1ccco1)c1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OC(c1ccco1)c1ccccc1Cl
Reaction time: 1 h
Yield: 70.3 %

Procedure:
Portions of sodium borohydride (total 15 g.) were added over an hour to a stirred solution of 2-(2-chlorobenzoyl)furan (prepared as hereinbefore described; 100 g.) in methanol (500 ml.) at 10°-25° C. After stirring for 1 hour, the solution was heated briefly to the boiling point and, when effervescence had ceased, sodium hydroxide solution (2N, 100 ml.) was added. The solution was heated at reflux for 30 minutes, diluted with water (1 liter) and extracted with diethyl ether (4 × 150 ml.). The combined extracts were washed with water (2 × 100 ml.), dried over sodium sulphate, filtered and evaporated to a clear oil, which was distilled to give (±) 2-(2-chloro-α-hydroxybenzyl)furan (71 g.), b.p. 136° C./0.1 mm.Hg, as a viscous yellow oil.
Reaction SMILES: C(N(CC)C(C1C=C(C2C=NN(CCCO)C=2)C=CC=1NC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(O)OCC)=CC=2OC)N=1)=O)C.[F:50][C:51]1[C:59]([C:60]2[CH:61]=[N:62][N:63]([CH2:65][CH2:66][CH2:67][OH:68])[CH:64]=2)=[C:58]2[C:54]([C:55](=[O:70])[N:56]([CH3:69])[CH2:57]2)=[C:53]([NH:71][C:72]2[C:77]([C:78]([F:81])([F:80])[F:79])=[CH:76][N:75]=[C:74]([NH:82][C:83]3[CH:97]=[CH:96][C:86]([CH2:87][P:88](=[O:95])([O:92]CC)[O:89][CH2:90][CH3:91])=[CH:85][C:84]=3[O:98][CH3:99])[N:73]=2)[CH:52]=1>>[F:50][C:51]1[C:59]([C:60]2[CH:61]=[N:62][N:63]([CH2:65][CH2:66][CH2:67][OH:68])[CH:64]=2)=[C:58]2[C:54]([C:55](=[O:70])[N:56]([CH3:69])[CH2:57]2)=[C:53]([NH:71][C:72]2[C:77]([C:78]([F:81])([F:79])[F:80])=[CH:76][N:75]=[C:74]([NH:82][C:83]3[CH:97]=[CH:96][C:86]([CH2:87][P:88](=[O:92])([OH:95])[O:89][CH2:90][CH3:91])=[CH:85][C:84]=3[O:98][CH3:99])[N:73]=2)[CH:52]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cc(F)c(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Agent: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cc(F)c(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1

Procedure:
This compound was prepared analogously to Compound 3A using diethyl (4-{[4-({6-fluoro-7-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 31B). MS (ESI): m/z=694.21 [M+H]+. UPLC: tR=1.13 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.CN1CCOCC1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[C:28]([F:36])[CH:27]=1>ClCCl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[CH:10]=[CH:11][C:12]=2[O:16][CH3:17])(=[O:33])=[O:34])=[C:28]([F:36])[CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1N
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)aniline (D4) (1.20 g, 5.09 mmol) in dichloromethane (35 ml) was treated with morpholinomethyl-polystyrene HL resin (2.43 g, 4.2 mmol/g loading, 10.2 mmol) followed by 4-bromo-2-fluorobenzenesulfonyl chloride (2.79 g, 10.2 mmol). The resulting solution was stirred at room temperature overnight, the resin was then filtered off, the solvent evaporated in vacuo and the residue was then passed through an SCX column eluting first with methanol and then by 2M ammonia in methanol. The basic fractions were combined and solvent evaporated in vacuo to afford a crude product which was dry loaded onto a column and purified further by chromatography using a Flashmaster and an elution gradient of 0 to 10% methanol in dichloromethane The relevant fractions were collected, combined and solvent evaporated to afford the title compound (E103). MS (ES+) m/e 472/474 [M+H]+.
Reaction SMILES: S(Cl)(C)(=O)=O.C([N:8](CC)CC)C.[CH2:13]([O:15][C:16](=[O:33])[C@@H:17]1[CH2:21][C@@H:20]([O:22][CH2:23][CH2:24]O)[CH2:19][N:18]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH3:14].[N-]=[N+]=[N-].[Na+].[Cl-].[Sn](Cl)(Cl)(Cl)Cl.C1(S)C=CC=CC=1>ClCCl.C(OCC)(=O)C>[CH2:13]([O:15][C:16](=[O:33])[C@@H:17]1[CH2:21][C@@H:20]([O:22][CH2:23][CH2:24][NH2:8])[CH2:19][N:18]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH3:14]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)[C@@H]1C[C@@H](OCCO)CN1C(=O)OC(C)(C)C
Agent: CS(=O)(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: Sc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1C[C@@H](OCCN)CN1C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
This transformation was done in three steps without characterizing the individual intermediates. Mesyl chloride (921 μl, 5 eq.) and triethylamine (1.66 mL, 5 eq.) were quickly added to a solution of N-(tert-butoxycarbonyl)-trans-4-(2-hydroxyethoxy)-L-proline ethyl ester (721 mg, 2.4 mmol) in dichloromethane (25 mL) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at that temperature for 1 hour, diluted in dichloromethane, washed twice with 1 N HCl, twice with sat NaHCO3, twice with brine, dried (Na2SO4) and concentrated. The crude residue (0.9 g) was dissolved in dimethylformamide (25 mL) and sodium azide (2.48 g, 16 eq.) and anunonium chloride (1.27 g, 10 eq.) were added. The reaction mixture was stirred at 90° C. for 16 h. after which it was cooled and concentrated under reduced pressure and the residue partitioned between dichloromethane and water. The aqueous layer was extracted twice with dichloromethane and the combined organic layers were washed twice with water, twice with brine, dried (Na2SO4) and concentrated. The crude residue (0.76 g) was dissolved in anhydrous tetrrhydrofuran (10 mL) and dry tin chloride (661 mg, 1.5 eq.), thiophenol (1.43 mL, 6 eq.) and triethylamine (4.5 eq.) were added. The reaction mixture was stirred at 25° C. for Ihour, then poured into ethyl acetate and washed with 1 N HCl, 1 N NaOH, brine, dried (Na2SO4) and concentrated. The product (668 mg, 92%) was used crude: 1H NMR (300 MHz, CDCl3) δ 1.39 (m, 3H), 1.53, 1.58 (2s, 9H), 2.16 (m, 1H), 2.43 (m, 1H), 2.95 (m, 2H), 3.57 (m, 2H), 3.69 (m, 2H), 4.18 (m, 1H), 4.24 (m, 2H), 4.40 (m, 1H).
Reaction SMILES: C(O[Si](OCC)(OCC)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:11]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[CH:6]=1)C.Br[C:28]1[CH:33]=CC=CC=1Br.[I-].[Cs+]>>[CH2:13]([O:12][Si:11]([O:18][CH2:33][CH3:28])([O:15][CH2:16][CH3:17])[C:6]1[CH:5]=[CH:10][CH:9]=[CH:8][C:7]=1[Si:11]([O:12][CH2:13][CH3:14])([O:15][CH2:16][CH3:17])[O:18][CH2:19][CH3:20])[CH3:14]
Reactant: Brc1ccccc1Br
Reactant: CCO[Si](OCC)(OCC)c1cccc([Si](OCC)(OCC)OCC)c1
Agent: [Cs+]
Agent: [I-]
Product: CCO[Si](OCC)(OCC)c1ccccc1[Si](OCC)(OCC)OCC

Procedure:
The procedure used for the preparation of 1,3 di(triethoxysilyl) benzene was followed using 1,2 dibromobenzene (100.0 g, 0.424 mg). The product after two distillations was a clear colorless oil (11.9 g, 7%). IR (Neat, CsI, cm-1): 3040 w, 2963 s, 2920 s, 2880 s, 730 w, 1480 w, 1436 m, 1426 w, 1310 w, 1290 w, 1160 s, 1100 vs, 955 s, 780 s, 755 s, 718 m, 700 m, 668 w, 515 m, 484 m. 1H NMR (benzene-d6, 22° C., 300 MHz ): δ 1.21 (t, J=7.2 Hz, 18 H, OCH2CH3), 3.91 (q, J=7.2 Hz, 12H, OCH2CH3), 7.29 (dd, J=5.7 Hz, 2H, C6H4), 8.12 (dd, J=5.7 Hz, 2H, C6H4). 13C{:H} NMR (benzene-d6, 22° C., 75.5 MHz ): δ 18.44 (OCH2CH3), 58.87 (OCH2CH3), 129.25, 137.19, 138.97 (C6H4).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@H:16]([NH2:20])([CH2:18][CH3:19])[CH3:17].C([BH3-])#N.[Na+]>CO>[C@H:16]([NH:20][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1)([CH2:18][CH3:19])[CH3:17]
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: CC[C@@H](C)N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC[C@@H](C)NCc1ccc(Oc2ccccc2)cc1
Reaction time: 18 h
Yield: 76.4 %

Procedure:
4-Phenoxybenzaldehyde (8.13 g, 41 mmol) and (R)-sec-butylamine (3 g, 41 mmol) were dissolved in methanol (137 mL) under nitrogen at room temperature. Sodium cyanoborohydride (2.58 g) was added, and stirring was continued for 18 hours. The solvent was removed, and the residue was suspended in ether, washed with brine and dried over Na2SO4. The ether was evaporated, and the crude product was chromatographed on silica gel eluting with 3% methanol in methylene chloride to provide 8.0 g (77%) of the title compound as a colorless oil.