Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH3:11])=[CH:4][CH:3]=1.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.[Cl-].[Cl-].[Ca+2]>ClCCCl>[C:12]1([CH:9]([CH2:10][CH3:11])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][O:19]3)=[CH:7][CH:6]=2)=[O:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C1=COCCC1
Reactant: CCC(C(=O)c1ccc(O)cc1)c1ccccc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCC(C(=O)c1ccc(OC2CCCCO2)cc1)c1ccccc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
A mixture of compound 8 (908 g, 3.78 mol) in 1,2-dichloroethane (6.36 L) stirred at 30° C. was treated with dihydropyran (1590 g, 18.9 mol) in a single portion. The resulting solution was treated with CaCl2 (83.8 g, 0.76 mmol) in a single portion and the reaction warmed at 70° C. for 16 h. The reaction was filtered through celite and the solid washed with 1,2-dichloroethane (2×900 mL). The filtrate was concentrated by distillation to approximately 5 L and heptane added (9 L). The reaction solution was again concentrated by distillation to approximately 7 L and then cooled slowly and held at 5° C. for 1 h. The solids were filtered, washed with heptane (2×1.8 L) and dried in vacuo at 40° C. to afford 1134 g (93%) of 9 as a solid. 1HNMR (400 MHz, DMSO-d6): δ 0.79 (t, J=7.3 Hz, 3H), 1.49-1.83 (m, 8H), 2.03 (h, J=7.0 Hz, 1H), 3.49-3.66 (m, 2H), 4.65 (t, J=7.2 Hz, 1H), 7.02 (d, J=8.4 Hz, 2H), 7.13-7.30 (m, 5H), 7.97 (d, J=8.4 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH3:36])[CH:28]4[CH2:31][CH:30]([CH2:32][C:33]([OH:35])=O)[CH2:29]4)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.[C:43]([C:47]1[CH:48]=[C:49]([NH2:54])[C:50]([NH2:53])=[CH:51][CH:52]=1)([CH3:46])([CH3:45])[CH3:44].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>CN(C)C=O>[NH2:54][C:49]1[CH:48]=[C:47]([C:43]([CH3:45])([CH3:44])[CH3:46])[CH:52]=[CH:51][C:50]=1[NH:53][C:33](=[O:35])[CH2:32][CH:30]1[CH2:29][CH:28]([N:27]([CH2:26][C@@H:18]2[C@@H:19]3[C@@H:20]([O:21][C:22]([CH3:25])([CH3:24])[O:23]3)[C@H:16]([N:13]3[C:9]4[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]5[CH:37]=[CH:38][C:39]([O:41][CH3:42])=[CH:40][C:3]=5[O:2][CH3:1])[C:8]=4[CH:15]=[CH:14]3)[O:17]2)[CH3:36])[CH2:31]1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(C)C3CC(CC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(C)C3CC(CC(=O)Nc4ccc(C(C)(C)C)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
A solution of 2-(3-((((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)acetic acid and 4-tert-butylbenzene-1,2-diamine (89.4 mg, 0.545 mmol) in N,N-dimethylformamide (4.5 mL) was treated with N,N-diisopropylethylamine (0.261 mL, 1.50 mmol) dropwise followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (259 mg, 0.681 mmol). The solution was allowed to stir at room temperature for 18 h during which time LCMS indicated the starting material had been consumed. The reaction mixture was concentrated under high vac. The residue was taken up in 30 mL ethyl acetate and 20 mL 1/1 H2O/sat NaHCO3 solution. The mixture was extracted and the aqueous phase was washed with 35 mL ethyl acetate. The combined organic phase was washed with two 20 mL portions of H2O, and 20 mL brine. The organic phase was dried over Na2SO4, filtered and concentrated to yield a tannish brown glass/stiff foam. The crude material was purified by flash chromatography (35 g silica gel; 4% 7N NH3 in CH3OH/CH2Cl2) to yield the title compound (272 mg, 82%) as a light tan glass/stiff foam which was a mixture of regioisomeric amides: MS (ESI+) for C41H53N7O6 m/z 728.8 (M+H)+; MS (ESI−) for C41H53N7O6 m/z 726.9 (M−H)−; HPLC purity >95%, (ret. time, 3.14, 3.17 min) two peaks observed due to amide regioisomers.
Reaction SMILES: [O:1]=[C:2]([NH:14][CH2:15][C:16]1[NH:17][C:18](=[O:26])[C:19]2[CH2:25][O:24][CH2:23][CH2:22][C:20]=2[N:21]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12]C)=[O:11])[CH2:6][CH2:5]1.[OH-].[Na+].Cl>CO.O>[O:1]=[C:2]([NH:14][CH2:15][C:16]1[NH:17][C:18](=[O:26])[C:19]2[CH2:25][O:24][CH2:23][CH2:22][C:20]=2[N:21]=1)[CH2:3][N:4]1[CH2:5][CH2:6][CH:7]([C:10]([OH:12])=[O:11])[CH2:8][CH2:9]1
Reactant: COC(=O)C1CCN(CC(=O)NCc2nc3c(c(=O)[nH]2)COCC3)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(CN1CCC(C(=O)O)CC1)NCc1nc2c(c(=O)[nH]1)COCC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of methyl 1-(2-oxo-2-((4-oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methylamino)ethyl)piperidine-4-carboxylate (1.2 g, 3.3 mmol) in methanol (5 mL) was added sodium hydroxide (0.4 g, 10 mmol) in water (5 mL). The mixture was stirred at ambient temperature for 24 h, neutralized with HCl (37%) until pH 5˜7 and the solvent was evaporated under reduced pressure to give a white solid which was used directly to the next step. 1H NMR (400 MHz, CD3OD) δ 4.48 (s, 2H), 4.38 (s, 2H), 3.95 (t, J=5.8 Hz, 2H), 3.24-3.36 (m, 1H), 3.10 (d, J=12.1 Hz, 2H), 2.67 (t, J=5.6 Hz, 2H), 2.45 (td, J=11.4, 2.5 Hz, 2H), 2.25-2.39 (m, 1H), 1.77-2.04 (m, 5H).
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[C:6]([CH2:13][CH:14]=[CH2:15])[CH:5]=1.[Li+].[OH-].[OH-].[Na+]>>[CH2:13]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH3:11])[C:7]=1[OH:12])[C:3]([OH:16])=[O:2])[CH:14]=[CH2:15]
Reactant: C=CCc1cc(C(=O)OC)cc(OC)c1O
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Product: C=CCc1cc(C(=O)O)cc(OC)c1O
Reaction time: 18 h

Procedure:
3-Allyl-4-hydroxy-5-methoxybenzoic acid was prepared from 3-allyl-4-hydroxy-5-methoxybenzoic acid methyl ester (Example 1, Step 2) using Method E. In this method LiOH was replaced with NaOH and the reaction was conducted at room temperature for 18 h. The product was extracted with ether. The crude product was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([Br:10])=[CH:4][N:3]=1.N1C=CC=CC=1.[Cl:17][CH2:18][C:19](Cl)=[O:20]>CCOCC>[CH3:9][O:8][C:7]1[C:2]([NH:1][C:19](=[O:20])[CH2:18][Cl:17])=[N:3][CH:4]=[C:5]([Br:10])[CH:6]=1
Reactant: O=C(Cl)CCl
Reactant: COc1cc(Br)cnc1N
Solvent: c1ccncc1
Solvent: CCOCC
Product: COc1cc(Br)cnc1NC(=O)CCl
Reaction time: 0.5 h

Procedure:
A solution of 2-amino-3-methoxy-5-bromopyridine (20.3 grams) in absolute ether (200 ml) is charged into a glass reaction vessel equipped with mechanical stirrer and addition funnel. The solution is cooled to a temperature of about 5° C and pyridine (20 ml) is added thereto. A solution of chloroacetyl chloride (11.3 grams) in ether (50 ml) is then slowly added, with stirring, to the flask over a period of about 30 minutes resulting in the formation of a precipitate. The temperature of the reaction mixture is kept below about 10° C during the addition of the chloroacetyl chloride and stirring is continued thereafter for a period of about 1 hour to ensure the completion of the reaction. The precipitate which has formed is then recovered by filtration and is washed first with aqueous potassium carbonate and then with water. The washed product is then dried in a vacuum desiccator to yield the desired product N-(3-methoxy-5-bromo-2-pyridyl)-α-chloroacetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:14][O:15][CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29](OB(O)O)[CH:30]=[CH:31][CH:32]=1)=[O:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:14][O:15][CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:31]4[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=4)[C:25]([O:24][CH3:23])=[O:26])[CH2:18]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1COCC1CCCNC1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Product: COC(=O)c1cccc(N2CCCC(COCc3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Yield: 79.4 %

Procedure:
Using 3-[[2-(4-chlorophenyl)-4-methylthiazol-5-yl]methoxymethyl]piperidine (62.2 mg, 0.185 mmol) and 3-(methoxycarbonyl)phenylboric acid (66.6 mg, 0.370 mmol), the same procedure was followed as in Example 2 to obtain 69.2 mg (79%) of the desired compound as a colorless oil.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[Cl:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[N:14]=C(S(C)(=O)=O)[N:12]=1.Cl>O1CCCC1.O>[NH:3]([C:1]1[N:12]=[C:11]([Cl:10])[CH:16]=[C:15]([O:17][CH3:18])[N:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=CNc1ccccc1
Reactant: COc1cc(Cl)nc(S(C)(=O)=O)n1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)nc(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
1.8 g of formanilide was dissolved in 50 ml of tetrahydrofuran, and 0.4 g of sodium hydride from which the oily matter had been removed beforehand with n-hexane was slowly added to the resulting solution at 10° to 20° C. while cooling with ice water. To the suspension thus obtained was added 3 3 g of 4-chloro-2-methanesulfonyl-6-methoxypyrimidine, and the mixture was stirred for 1 hour at room temperature. Then, 15 ml of 4N hydrochloric acid was added, and reaction was effected for 1 hour under reflux. The reaction liquid was poured in water, extracted with ether, and the ether layer was washed with water, dried over magnesium sulfate, and then the ether was stripped by concentration The residual crystals were recrystallized from n-hexane, and 4.0 g of 2-anilino-4-chloro-6-methoxypyrimidine was obtained (yield 87%). Melting point: 101°-103° C.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([Br:21])[CH:15]=1.[C:22](=[O:24])=[O:23]>C1COCC1.CCOCC>[Br:13][C:14]1[CH:15]=[C:16]([Br:21])[CH:17]=[C:18]([F:20])[C:19]=1[C:22]([OH:24])=[O:23]
Reactant: O=C=O
Reactant: Fc1cc(Br)cc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: O=C(O)c1c(F)cc(Br)cc1Br
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of n-BuLi (20 mL, 50.0 mmol) was added dropwise to a solution of diisopropylamine (5.6 g, 55.0 mmol) in 200 mL of THF at −70° C. The mixture was stirred at 0° C. for 15 minutes and then recooled to −70° C. A solution of 1,3-dibromo-5-fluorobenzene (12.7 g, 50.0 mmol, in 50 mL of THF) was added dropwise. The resulting mixture was stirred at −70° C. for 2 hours then poured into fresh dry ice and stirred overnight. The mixture was diluted with 1 L of ether and washed with water twice. The combined water layer was washed with ether then acidified to pH=2 with hydrochloric acid and extracted with EtOAc twice. The combined EtOAc layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to give 2,4-dibromo-6-fluorobenzoic acid as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6][CH2:5]2.[CH:12]([O:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18](O)=[O:19])([CH3:14])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:18]([C:17]1[CH:21]=[C:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:23]=[CH:24][C:16]=1[O:15][CH:12]([CH3:14])[CH3:13])=[O:19])[CH2:6][CH2:5]2
Reactant: Clc1ccc2c(c1)CCNC2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2cc(Cl)ccc2C1

Procedure:
Prepared in analogy to example 1.1 from 6-chloro-1,2,3,4-tetrahydro-isoquinoline (CA [33537-99-4]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:19])=[C:6]([CH:8]=[C:9]2[C:13]([CH3:15])([CH3:14])[O:12][C:11]([CH3:17])([CH3:16])[C:10]2=[O:18])[CH:7]=1.[OH:20]O.[OH-].[Li+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:19])=[C:6]([CH:8]2[C:9]3([C:10](=[O:18])[C:11]([CH3:17])([CH3:16])[O:12][C:13]3([CH3:14])[CH3:15])[O:20]2)[CH:7]=1
Reactant: OO
Reactant: CC1(C)OC(C)(C)C(=Cc2cc(Br)ccc2I)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)OC(C)(C)C2(OC2c2cc(Br)ccc2I)C1=O
Temperature: 35 °C
Reaction time: 3 h

Procedure:
To a solution of 4-[1-(5-bromo-2-iodophenyl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (1.18 g, 2.73 mmol) in methanol (50 ml) at 35 ° C. is added 50% aqueous hydrogen peroxide solution (0.31 ml, 5.46 mmol), followed immediately by 2M aqueous lithium hydroxide (0.34 ml, 0.68 mmol). This mixture is stirred at 35 ° C. for 3 hours, then quenched with saturated aqueous sodium metabisulfite and extracted with dichloromethane. The organic phase is separated, and the aqueous phase extracted again with dichloromethane. All organics are combined then evaporated under reduced pressure to afford 2-(5-bromo-2-iodophenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one as an oil which is used directly in the next step.
Reaction SMILES: [C:1]([S:14](F)(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[CH2:18]([NH2:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(N(CC)CC)C>O>[C:1]([S:14]([NH:24][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCN
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 65 °C
Yield: 81.3 %

Procedure:
A 2-liter flask fitted with a thermocouple, overhead stirrer, dropping funnel and heating mantle was charged with C4F9SO2F (543 g, 1.80 mole). To this stirred material was slowly added a mixture of hexylamine (194.0 g, 1.90 mole) and triethylamine (194.0 g, 1.90 mole); the ensuing mixture was stirred and heated at 65° C. for 2 hours. Water (555.0 g) was then added, and stirred for an additional 30 minutes. The lower phase was separated, put into a flask and heated to 60° C. To this heated mixture was added sulfuric acid (50 g concentrated sulfuric and 500 g water). The lower phase of the resulting two-phase mixture was then separated, washed with water (500 g), and placed in a flask with a one-plate distillation head. The flask was heated to 80° C. at 20-25 mm Hg (2.7-3.3 kPa) and the distillate collected over a period of one hour. The material that remained in the flask was further distilled at 8 mm Hg (0.4 kPa) and a pot temperature of 138-143° C., yielding C4F9SO2NH(CH2)5CH3 (561.0 g). NMR and GC/MS analyses were consistent with the indicated material.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)C.[O-]CC.[Na+].Cl[C:20]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)([CH3:24])[CH2:21][S:22][CH3:23].ClCC(C1C=CC(F)=CC=1)(C)SC>C(O)C>[F:31][C:28]1[CH:27]=[CH:26][C:25]([C:20]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])([CH3:24])[CH2:21][S:22][CH3:23])=[CH:30][CH:29]=1
Reactant: CSCC(C)(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: CSC(C)(CCl)c1ccc(F)cc1
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)C(C)(CSC)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of diethyl malonate (12 mL, 81 mmol) in ethanol (40 mL) was added dropwise 21% sodium ethoxide ethanol solution (29 mL, 77 mmol) under nitrogen atmosphere under ice-cooling. The mixture was warmed to room temperature, stirred for 1 hour, and cooled again with ice. The crude product (73 mmol) of 1-(1-chloro-1-methyl-2-methylsulfanyl-ethyl)-4-fluorobenzene or 1-(2-chloro-1-methyl-1-methylsulfanyl-ethyl)-4-fluorobenzene obtained in Example 1-3 was added dropwise to the mixture while maintaining a temperature below 4° C. The obtained solution was stirred for 1 hour at room temperature and concentrated under reduced pressure. The residue was neutralized by adding a 2N aqueous hydrochloric acid solution and the aqueous layer was extracted with ethyl acetate (50 mL). The organic layer was dried over magnesium sulfate, filtrated and the solvent was evaporated. Then the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=20:1 to 5:1) to give the title compound (24 g, yield 84%) as a pale-yellow oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4]1.Br[CH2:19][CH2:20][CH2:21][Cl:22]>CN(C)C=O>[Cl:22][CH2:21][CH2:20][CH2:19][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4]1
Reactant: ClCCCBr
Reactant: COC(=O)CCc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1cn(CCCCl)c2ccccc12
Temperature: 55 °C
Reaction time: 16 h
Yield: 83.8 %

Procedure:
Sodium hydride (60% dispersion) (236 mg, 5.91 mmol, 1.2 equiv) was slowly added to a cold mixture of methyl 3-(1H-indol-3-yl)propanoate (2 g, 4.92 mmol, 1 equiv) in N,N-dimethylformamide. After all the sodium hydride has reacted, 1-bromo-3-chloropropane (1.94 ml, 19.68 mmol, 4 equiv) was added and the reaction stirred at 55° C. for 16 h. Upon cooling the reaction was partitioned between water and ethyl acetate. The organic layer was further washed with 1N hydrogen chloride, brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified using the Biotage flash chromatography system (SNAP 50 g cartridge, Rf=0.5, gradient—1%-10% ethyl acetate in hexanes) to afford the title compound as a yellow oil (1.154 g, 83%); 1H NMR (400 MHz, DMSO-d6): δ 2.12-2.27 (m, 2H); 2.65-2.70 (m, 2H); 2.93-2.98 (m, 2H); 3.38-3.54 (m, 2H); 3.58 (s, 3H); 4.08-4.12 (m, 2H); 4.21-4.25 (m, 2H); 7.02 (t, 1H, J=7.6 Hz); 7.12-7.15 (m, 2H); 7.43 (dd, 1H, J=3.2 and 2.8 Hz); 7.52-7.55 (m, 1H); MS for C15H18ClNO2 m/z 280 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9](=O)[CH2:8][CH2:7][CH2:6][N:5]2[CH:11]=1.[NH2:12][C@H:13]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:14]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C:15](OCC)=[O:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([N-]C(C)C)(C)C.[Li+]>C1(C)C=CC=CC=1.O1CCCC1.O>[Si:21]([O:20][C@H:14]1[C:15](=[O:16])[C:8]2[CH2:7][CH2:6][N:5]3[CH:11]=[C:2]([CH3:1])[N:3]=[C:4]3[C:9]=2[NH:12][C@@H:13]1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: Cc1cn2c(n1)C(=O)CCC2
Reactant: CCOC(=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@H](N)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cn2c(n1)C1=C(CC2)C(=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](c2ccccc2)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
19.4 g (128.3 mmol) of 2-methyl-6,7-dihydro-5H-imidazo[1,2-a]pyridin-8-one, 42.07 g (130.2 mmol) of ethyl (2R,3R)-3-amino-2-(t-butyldimethylsilanyloxy)-3-phenylpropionate and 0.65 g of p-toluenesulfonic acid monohydrate are boiled under reflux in a water separator for 1.5 h in 100 ml of absolute toluene. The solution is cooled to room temperature and treated with 100 ml of absolute tetrahydrofuran. 154 ml of 2M LDA (lithium diisopropylamide) solution (THF) are then added dropwise to the reaction solution, which is cooled to −25° C. After the LDA addition, the temperature is allowed to rise to 0° C. and the mixture is stirred further at 0° C. for 1 h. The reaction solution is washed once at room temperature with 200 ml of saturated ammonium chloride solution, once with 50 ml of saturated ammonium chloride solution and once with water. The organic phase is concentrated and chromatographed on silica gel (petroleum ether/ethyl acetate 2:1). The concentrated product fractions are dried in a high vacuum. 50.8 g (97% of theory) of the title compound are obtained.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH2:15][N:16]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[CH3:17])[CH:12]=[C:11]([Cl:23])[C:10]=1[F:24])(C)(C)C.Cl>O1CCOCC1>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:12]=[C:11]([Cl:23])[C:10]=1[F:24])[CH2:15][N:16]([CH3:17])[CH2:18][CH2:19][N:20]([CH3:22])[CH3:21]
Reactant: CN(C)CCN(C)Cc1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)CCN(C)Cc1cc(Cl)c(F)c(CN)c1

Procedure:
was prepared according to Scheme C2 (step D) from (3-chloro-5-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-2-fluoro-benzyl)-carbamic acid tert-butyl ester (228 mg, 0.51 mmol) and 4N HCl in dioxane. MS (LC-MS): 274.0 [M]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][C:13](=[N:15][O:16][CH2:17][CH:18]=[CH2:19])[CH3:14])=[C:9]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:25]1(=O)[CH2:30][CH2:29][CH2:28][C:27](=[O:31])[CH2:26]1.Cl.CN(C)CCCN=C=NCC.CN(C1C=CC=CN=1)C>>[Cl:1][C:2]1[C:10]([O:11][CH2:12][C:13](=[N:15][O:16][CH2:17][CH:18]=[CH2:19])[CH3:14])=[C:9]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:25]1[CH2:30][CH2:29][CH2:28][C:27](=[O:31])[CH:26]=1)=[O:5]
Reactant: C=CCON=C(C)COc1c(S(=O)(=O)CC)ccc(C(=O)O)c1Cl
Reactant: O=C1CCCC(=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Product: C=CCON=C(C)COc1c(S(=O)(=O)CC)ccc(C(=O)OC2=CC(=O)CCC2)c1Cl

Procedure:
0.526 g (1.40 mmol) of 2-chloro-3-(2-allyloxyiminopropyloxy)-4-ethanesulfonylbenzoic acid, 0.173 g (1.50 mmol) of cyclohexane-1,3-dione, 0.274 g (1.40 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 0.002 g of dimethylaminopyridine were reacted analogously to preparation c).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1.CO.C(OCC)(=O)C>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:8]=[CH:7][C:6]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(-c2ccc(C=O)cc2OC)cc1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(CN3CCOCC3)cc2OC)cc1

Procedure:
A mixture of Example 122I (135 mg, 0.50 mmol), morpholine (100 mg), 1M sodium cyanoborohydride in THF (1 mL) in methanol (2 mL) and acetic acid (0.3 mL) was stirred for 18 hours, diluted with ethyl acetate (100 mL), washed sequentially with 2M sodium carbonate (10 mL), water (20 mL), and brine (10 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 30-100% ethyl acetate/hexanes to provide the desired product. MS (DCI(+)) m/e 342 (M+H)+.