Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[OH:3][C:4]([CH3:24])([CH3:23])[C:5]#[C:6][C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[N:13]([CH3:22])[CH2:12][C:11]=12.[CH3:25]I>CS(C)=O>[CH3:25][O:3][C:4]([CH3:24])([CH3:23])[C:5]#[C:6][C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[N:13]([CH3:22])[CH2:12][C:11]=12
Reactant: CN1Cc2c(C#CC(C)(C)O)ncn2-c2ccccc2C1=O
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COC(C)(C)C#Cc1ncn2c1CN(C)C(=O)c1ccccc1-2
Reaction time: 1 h

Procedure:
4.58 g (80 mmol) of freshly powdered potassium hydroxide was suspended in 65 ml of dimethyl sulfoxide and cooled to 5°. 5.67 g (19.2 mmol) of 4,5-dihydro-3-(3-hydroxy-3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one and 5.47 g (38.5 mmol) of methyl iodide were added thereto in succession. The cooling bath was removed and the mixture was stirred for a further 1 hour. The reaction mixture was evaporated and the residue was chromatographed on silica gel while eluting with methylene chloride/methanol (19.5:0.5). After crystallization from tert.-butyl methyl ether there was obtained 4,5-dihydro-3-(3-methoxy-3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 136°-137°.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1Br.[OH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>[OH-].[Na+]>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[N:12]1[CH2:13][CH2:14][CH:9]([OH:8])[CH2:10][CH2:11]1
Reactant: OC1CCNCC1
Reactant: Cn1ccnc1Br
Agent: [Na+]
Agent: [OH-]
Product: Cn1ccnc1N1CCC(O)CC1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
A mixture of N-methyl-2-bromoimidazole (7.3 g, 45.3 mmol) and 4-hydroxypiperidine (11.4 g, 113 mmol, 2.5 eq) was stirred at 140° C. for 16 h. After cooling to room temperature, the reaction mixture was diluted with 10% aq. NaOH solution to pH 12. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water (20 mL) followed by brine (20 mL), dried over sodium sulfate, filtered, and evaporated under vacuum. The solid residue was purified by column chromatography by eluting with 5% to 20% methanol in dichloromethane to yield the title compound as yellow solid. 1H NMR (CDCl3, 300 MHz): δ=6.64 (d, J=0.9 Hz, 1H), 6.75 (d, J=0.9 Hz, 1H), 3.85-3.84 (m, 1H), 3.47 (s, 3H), 3.24-3.22 (m, 2H), 2.94-2.92 (m, 2H), 2.01-1.98 (m, 2H), 1.71-1.69 (m, 2H). MS (ES+): m/z=182.28 (100) [MH+]. HPLC: tR=0.74 & 1.13 min (verypolar—5 min, ZQ3).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([C:15](OC)=O)=[CH:8][CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:5]=2[NH:4][C:3]1=[O:19].[CH2:20]([Mg]Br)[CH3:21].[CH2:24](OCC)[CH3:25].Cl>O1CCCC1.O.CO>[CH2:24]([C:15]([C:7]1[C:6]2[N:2]([CH3:1])[C:3](=[O:19])[NH:4][C:5]=2[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=1)=[CH:20][CH3:21])[CH3:25]
Reactant: CC[Mg]Br
Reactant: CCOCC
Reactant: COC(=O)c1ccc(C(F)(F)F)c2[nH]c(=O)n(C)c12
Agent: Cl
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC=C(CC)c1ccc(C(F)(F)F)c2[nH]c(=O)n(C)c12
Temperature: 45 °C
Reaction time: 16 h

Procedure:
To an ice-cooled solution of, methyl 3-methyl-2-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-benzimidazole-4-carboxylate (2.80 g, 10.2 mmol) in tetrahydrofuran (30 ml) was added a solution of 3M ethylmagnesium bromide in diethylether (13.6 ml, 40.8 mmol) dropwise and stirred at 45° C. for 16 h. Methanol and water were carefully added to decompose excess reagent. 2N hydrochloric acid was added and extracted with ethyl acetate. The extracts were washed with aqueous saturated sodium bicarbonate and water, dried over magnesium sulfate and concentrated in vacuo. Ethanol (40 ml) and conc. hydrochloric acid (10 ml) were added to the residue and the resulting mixture was heated at 80° C. for 6 h. The reaction mixture was concentrated in vacuo. Aqueous saturated sodium bicarbonate was added to the residue and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel with a 20% ethyl acetate/n-hexane to give 609 mg (2.14 mmol, 21%, cis/trans=3/1) of the title compound as a white powder.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:25][C:11]3[CH:12]=[N:13][C:14]([NH:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[O:18])=[CH:15][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C1COCC1.N1C=CC=CC=1>[CH:26]1([C:32]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[NH:25][C:11]4[CH:12]=[N:13][C:14]([NH:16][C:17]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=5)=[O:18])=[CH:15][C:10]=4[N:9]=3)=[CH:4][CH:3]=2)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1ccc(-c2nc3cc(NC(=O)c4ccccn4)ncc3[nH]2)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1cc2nc(-c3ccc(C(=O)C4CCCCC4)cc3)[nH]c2cn1)c1ccccn1
Yield: 49 %

Procedure:
A solution of amine 22 (0.040 g, 0.12 mmol) and cyclohexane carbonyl chloride (0.100 ml, 0.68 mmol) in dry THF-Pyridine (10 ml/0.300 ml) was stirred at room temperature overnight. A usual work-up as described earlier afforded the diamide 23 (0.025 g, 47%). M.p. 258° C.; 1H NMR (DMSO-d6, 500 MHz): δ 13.5 (1H, brs, NH), 10.60 (1H, brs, NH), 10.13 (1H, brs, NH), 8.78 (1H, d, J=5.0 Hz), 8.74 (1H, brs), 8.46 (1H, brs), 8.24 (1H, d, J=12.5 Hz), 8.115 (2H, d, J=8.0 Hz), 7.81 (2H, d, J=8.0 Hz), 7.74 (1H, dt, J=10.0 and 13.5 Hz), 2.37 (1H, m), 1.84-1.18 (10H, m); EIMS m/z: 441.4 (M+1), 439.6 (M−1); Anal (C25H24N6O2×1.10 H2O) C, H, N.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:15]1[CH:16]=[CH:17][C:18]2[O:22][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:20][C:19]=2[CH:27]=1.O.[Cl:29]CCl>C(OCC)C>[Cl:29][CH:2]1[CH2:3][N:4]([S:23]([C:21]2[O:22][C:18]3[CH:17]=[CH:16][CH:15]=[CH:27][C:19]=3[CH:20]=2)(=[O:24])=[O:25])[CH2:5][CH2:6][NH:1]1
Reactant: C1CNCCN1
Reactant: O=S(=O)(Cl)c1cc2cc(Cl)ccc2o1
Reactant: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOCC
Product: O=S(=O)(c1cc2ccccc2o1)N1CCNC(Cl)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of piperazine (1.15 g, 13.4 mmol) and triethylamine (4.7 ml, 46.5 mmol) in dichloromethane (30 ml) was cooled to ˜5° C. and a solution of 5-chlorobenzofuran-2-sulphonyl chloride (1.69 g, 7.8 mmol) in dichloromethane (10 ml) was added. Stirring was continued for 15 mins, and the reaction mixture then allowed to warm to ambient temperature over 2 hrs with stirring. Water was added to the reaction mixture, and the organic layer separated; this was washed with water (twice), brine (once), then dried (MgSO4), filtered and evaporated to give a yellow gum. This was chromatographed (Merck Art 9385 silica, eluting with dichloromethane containing increasing amounts of methanol, up to 10% v/v) to give a yellow solid; trituration with diethyl ether gave 5-chlorobenzofuran-2-ylsulphonyl piperazine as a colourless solid (1.11 g) which was used without further purification, 1H NMR (CDCl3) δ=2.8-3.0 ppm (t, 4H), δ=3.2-3.4 ppm (t, 4H), δ=7.3 ppm (s, 1H), δ=7.45 ppm (dd, 2H), δ=7.7 ppm (s, 1H); MS (M+H)+ 301/303.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[NH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O.C(Cl)Cl>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:21])[N:14]=2)[CH:4]=[C:3]([C:2]([F:1])([F:24])[F:23])[CH:8]=1
Reactant: NN1CCCC1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NN1CCCC1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 1.7 %

Procedure:
A cold (−40° C.) solution of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.35 g) in 1:1 CH2Cl2:EtOAc (200 mL) was treated with 1-aminopyrrolidine HCl (0.134 g). The mixture was then treated with T3P (50% in EtOAc; 0.77 ml, 1.3 eq.) followed by the slow addition of DIPEA (0.51 ml, 3.0 eq.). The reaction mixture was stirred for 30 min at −40° C. before being quenched with ice-water, and extracted with EtOAc (3×20 mL). The combined organic layers were washed with aqueous saturated brine, dried with anhydrous Na2SO4 and concentrated under reduced pressure (35° C., 20 mmHg) to afford 0.275 g of crude solid. Purification by column chromatography on silica gel (60-120 mesh size) using MeOH in CH2Cl2 as mobile phase afforded the pure desired (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N-(pyrrolidin-1-yl)acrylamide (7.0 mg yield: 1.7%): 1H NMR (400 MHz, DMSO-d6) δ, 9.49 (s, 1H), 8.95 (s, 1H), 8.53 (s, 2H), 8.28 (s, 1H), 7.4-7.38 (d, J=7.6 Hz, 1H), 5.87-5.84 (d, J=10.4 Hz, 1H), 2.86-2.81 (m, 4H), 1.74-1.73 (m, 4H); LCMS for C17H16F6N5O [M+H]+420.33; found 420.13 (RT 7.76 min, purity: 92.4%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:12])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[I:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[O:20][C@@H:19]([C:24](O)=[O:25])[CH2:18][CH2:17]2.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.O>[OH:12][C@H:3]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][NH:1][C:24]([C@H:19]1[CH2:18][CH2:17][C:16]2[C:21](=[CH:22][CH:23]=[C:14]([I:13])[CH:15]=2)[O:20]1)=[O:25]
Reactant: NC[C@H](O)COc1ccccc1
Reactant: O=C(O)[C@H]1CCc2cc(I)ccc2O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(NC[C@H](O)COc1ccccc1)[C@H]1CCc2cc(I)ccc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
A solution containing (2S)-1-amino-3-phenoxy-2-propanol (Example 53, 11.97 mmol, 1.0 eq.), (2R)-6-iodo-3,4-dihydro-2H-chromene-2-carboxylic acid (Example 7, 11.97 mmol, 1.0 eq.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (23.98 mmol, 2.0 eq.), 1-hydroxybenzotriazole hydrate (23.94 mmol, 2.0 eq.), and triethylamine (23.94 mmol, 2.0 eq.) in CH2Cl2 (200 mL) was stirred at room temperature for 3 hours. To the resulting solution was added water and two-phase mixture was extracted with CH2Cl2. The organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, hexanes:EtOAc=2:1). The product was obtained as a white solid in 77% yield. MH+=454.1, retention time (LC-MS)=3.03 min.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].O=[C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:19][CH2:18]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>C(O)(=O)C>[O:14]=[C:13]1[NH:15][C:17]2([CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])[CH2:19][CH2:18]2)[NH:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)[S:4][C:3]1=2
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC2(CCN(C(=O)OCc3ccccc3)CC2)Nc2cc(-c3ccncc3)sc21
Temperature: 90 °C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.219 g, 1.00 mmol), benzyl 4-oxo-1-piperidinecarboxylate (0.700 g, 3.00 mmol), p-toluenesulfonic acid monohydrate (0.211 g, 1.10 mmol) and toluene (10.0 mL) was stirred for 2 h at 90° C. Then, acetic acid (10.0 mL) was added, and the mixture was stirred for 1 h at 80° C. After removal of the solvent at reduced pressure, the obtained residue was poured into aqueous sodium hydrogen carbonate (200 mL). Extraction with ethyl acetate (200 mL, 100 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave a solid. The solid was triturated with ethyl acetate/dichloromethane (1:1, 10 mL), and the precipitate was collected by filtration to afford the title compound (0.276 g, 64%) as a yellow solid:
Reaction SMILES: Cl[CH2:2][C:3]([NH:6][C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[CH3:16])=[O:8])([CH3:5])[CH3:4].[H-].[Na+].CO>C1COCC1.C(Cl)(Cl)Cl>[CH3:2][C:3]1([CH3:5])[CH2:4][N:9]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[CH3:16])[C:7](=[O:8])[NH:6]1
Reactant: Cc1ccncc1NC(=O)NC(C)(C)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccncc1N1CC(C)(C)NC1=O
Reaction time: 2 h
Yield: 93.9 %

Procedure:
1-(2-Chloro-1,1-dimethyl-ethyl)-3-(4-methyl-pyridin-3-yl)-urea (I-200d: 1 g, 4.149 mmol) in dry THF (5 mL) was added dropwise to a stirred mixture of NaH (298 mg, 6.208 mmol) in dry THF (10 mL) under argon atmosphere over a period of 10 minutes at 0° C. The resulting reaction mixture was stirred for 2 hrs. The reaction was monitored by TLC (5% MeOH in CHCl3). The reaction mixture was partitioned between water and ethylacetate. The organic layer was dried over Na2SO4 and concentrated to afford 800 mg of the product (94.33% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2([OH:25])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:21]2[CH2:22][CH2:23][CH2:24][C:19]([OH:25])([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[CH:14]=3)[CH2:20]2)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: COc1cccc(C2(O)CCCN(C(=O)c3ccc(Cl)cc3)C2)c1

Procedure:
The compound of Example 19 was prepared according to the general preparation protocol A from 4-chlorobenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH:15]1([NH2:18])[CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:18][CH:15]3[CH2:17][CH2:16]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: NC1CC1
Reactant: O=C1CCN(c2ncc(Cl)cn2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Clc1cnc(N2CCC(NC3CC3)CC2)nc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
1-(5-Chloropyrimidin-2-yl)piperidin-4-one (1.5 g) is dissolved in anhydrous dichloromethane (25 mL) and cyclopropylamine (0.42 g) is added followed by glacial acetic acid (0.80 mL). Sodium triacetoxyborohydride (1.8 g) is then added in one portion under nitrogen and the resulting mixture stirred at r.t. for 17 h. The mixture is diluted with dichloroemthane (25 mL) and extracted with 3 M HCl (75 mL and 50 mL). The combined HCI layers are cooled on ice and 4 M NaOH (100 mL) is added in portions until the mixture is strongly basic (pH ˜14). The mixture is then extracted with dichloroemthane (150 mL and 100 mL) and the combined dichloromethane layers are dried over Na2SO4, filtered and concentrated to yield the title compound. LC (method 21): tR=2.57 min; Mass spectrum (APCI): m/z=253 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][CH2:8][C:9]([O:11]CC)=O.O.[NH2:15][NH2:16]>C(O)(C)C>[NH3:1].[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][CH2:8][C:9]([NH:15][NH2:16])=[O:11]
Reactant: NN
Reactant: CCOC(=O)COc1ncccn1
Solvent: CC(C)O
Solvent: O
Product: N
Product: NNC(=O)COc1ncccn1

Procedure:
A mixture of ethyl 2-pyrimidinyloxyacetate (GB2373186, step i ex 368) (4.4 g, 24.15 mmol) and hydrazine hydrate (5 mL, 160 mmol) in isopropanol (30 mL) was heated under reflux for 1 hour. The mixture was then cooled and concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (100:0:0 to 100:10:1) to provide the title compound, 600 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24](C)[CH:23]=[C:22]4C=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[CH3:29][NH:30][CH2:31][C:32]([OH:34])=[O:33].[C:35](O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:29][N:30]([CH3:35])[CH2:31][C:32]([OH:34])=[O:33])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C=O)cn(C)c34)no2)cc1Cl
Reactant: CC(=O)O
Reactant: CNCC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CN(C)CC(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 40 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a stirred solution of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indole-3-carbaldehyde (D61) (200 mg), N-methylglycine (93 mg) and acetic acid (32 mg) in DCM (10 mL) was added NaBH(OAc)3 (223 mg). The reaction was stirred at 40° C. overnight. After cooled to room temperature, the reaction mixture was diluted with DCM (10 mL), washed with water (20 mL) and aqueous saturated sodium bicarbonate (20 mL). The organic phase was separated and dried over anhydrous sodium sulphate. After concentration, the residue was purified by Mass Directed Auto Prep to afford N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}-N-methylglycine (E52) (210 mg, TFA salt). δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 2.80 (3H, s), 4.01 (2H, s), 4.57 (2H, s), 4.90 (1H, m), 7.35 (1H, t), 7.46 (1H, d), 7.75 (1H, d), 8.01 (1H, d), 8.07 (1H, d), 8.21 (1H, dd), 8.39 (1H, d), 11.48 (1H, br s). MS (ES): C23H23ClN4O4 requires 454; found 366.1 (M—C3H6NO2+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([OH:12])[CH2:10][OH:11])=[CH:4][CH:3]=1.[C:13]1(C)[CH:18]=CC(S(O)(=O)=O)=C[CH:14]=1>CN(C=O)C.COC(OC)(C)C.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]2[CH2:10][O:11][C:13]([CH3:18])([CH3:14])[O:12]2)=[CH:6][CH:7]=1
Reactant: OCC(O)Cc1ccc(Br)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)OC
Solvent: CN(C)C=O
Product: CC1(C)OCC(Cc2ccc(Br)cc2)O1
Yield: 1994.1 %

Procedure:
A solution of 3-(4-bromo-phenyl)-propane-1,2-diol (1.41 g, 6.10 mmol) and p-toluenesulfonic acid (50 mg) in DMF (10 mL), 2,2-dimethoxypropane (10 mL) is stirred at rt for 2 h. The reaction mixture is diluted with sat. aq. NaHCO3 (150 mL) and extracted with diethyl ether (2×200 mL). The organic extracts are washed with water (200 mL), dried over MgSO4 and evaporated to give 4-(4-bromo-benzyl)-2,2-dimethyl-[1,3]dioxolane (1.57 g) as a pale brownish oil; LC-MS: tR=1.00 min.
Reaction SMILES: [C:1]1([CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:32]=[CH:33][CH:34]=2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:21][CH:20]=2)=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C[I:36].[C:37](OCC)(=O)C>CN(C=O)C>[I-:36].[CH3:37][N+:26]1([CH2:25][C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:16](=[O:17])[C:15]3[CH:32]=[CH:33][CH:34]=[C:13]([O:12][CH2:11][C:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH:4]=[CH:3][CH:2]=4)[CH:14]=3)=[CH:20][CH:21]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CCOC(C)=O
Reactant: CI
Reactant: O=C(Nc1ccc(CN2CCCCC2)cc1)c1cccc(OCc2cccc3ccccc23)c1
Solvent: CN(C)C=O
Product: C[N+]1(Cc2ccc(NC(=O)c3cccc(OCc4cccc5ccccc45)c3)cc2)CCCCC1
Product: [I-]
Temperature: 25 °C
Reaction time: 38 h

Procedure:
To 3-(1-naphthylmethoxy)-4′-(piperidinomethyl)benzanilide (950 mg) dissolved in DMF (8 ml) was added methyl iodide (394 μl), and the resulting mixture was stirred at room temperature for 38 hours. Ethyl acetate (200 ml) was added to this reaction mixture, and the resulting precipitate was collected by filtration to obtain 1-methyl-1-[4-[3-(1-naphthylmethoxy)benzoylamino]benzyl]piperidinium iodide (compound 89) (1.21 g) as colorless crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:14])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1.[H-].[Na+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>C1COCC1.CN(C=O)C.CCOC(C)=O>[C:22]([O:21][C:19](=[O:20])[CH2:18][O:1][CH2:2][CH2:3][N:4]([CH3:14])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CN(CCO)c1ccc([N+](=O)[O-])cn1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(CCOCC(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])cn1
Reaction time: 8 h

Procedure:
(2-Hydroxy-ethyl)-methyl-(5-nitro-pyridin-2-yl)-amine (350 mg, 1.77 mmol) in THF (15 mL) and DMF (2 mL) was stirred with 60% NaH in oil (142 mg, 4.44 mmol) for 1 hr. The mixture was cooled and to this was added tert-butyl bromoacetate (1.31 mL, 8.88 mmol). The reaction mixture was allowed to stir overnight. The mixture was diluted with EtOAc, extracted with H2O and dried over MgSO4. The EtOAc layer was filtered, evaporated to dryness and yielded 262 mg following flash chromatography. ES-MS calcd for C14H21N3O5 (m/e) 311.34, obsd 312 (M+H).
Reaction SMILES: [S:1]([C:5]1[C:6]([O:8][C:9](=[O:11])[CH:10]=1)=[O:7])([OH:4])(=[O:3])=[O:2].[CH2:12]([OH:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[OH-:25].[Na+:26]>O>[CH2:12]([O:24][C:5]([S:1]([OH:4])(=[O:3])=[O:2])([CH2:10][C:9]([O-:8])=[O:11])[C:6]([O-:25])=[O:7])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[Na+:26].[Na+:26].[Na+:26]
Reactant: CCCCCCCCCCCCO
Reactant: O=C1C=C(S(=O)(=O)O)C(=O)O1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCCOC(CC(=O)[O-])(C(=O)[O-])S(=O)(=O)O
Temperature: 100 °C
Yield: 64.2 %

Procedure:
Sulfomaleic anhydride (10 gm) is mixed with 80 gm (0.45 mole) of n-dodecanol and heated at 100°C for 14 hours. A solution of 7.04 gm of sodium hydroxide in 50 ml water is then added and the mixture heated at 60°C for 2 hours. The heated mixture is then extracted three times with 300 cc portions of acetone (at reflux) and the acetone insoluble fraction is then filtered, washed with additional acetone and dried to give 16.2 gm of the title compound (structure confirmed by NMR and ion exchange of a sample followed by titration with standard sodium hydroxide: neutralization equivalent: found 147.0, theory 149.3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:50][C@H:51]1[C@@H:55]([OH:56])[CH2:54][N:53]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:52]1>CC#N.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[CH:10][C:11]([C:14]([NH:50][C@H:51]3[C@@H:55]([OH:56])[CH2:54][N:53]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:52]3)=[O:16])=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@@H](O)C1
Reactant: O=C(O)c1cnc(-c2cccc(F)c2)nc1
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: CC#N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](O)[C@H](NC(=O)c2cnc(-c3cccc(F)c3)nc2)C1
Reaction time: 2 h
Yield: 140.5 %

Procedure:
To a solution of 2-(3-fluorophenyl)pyrimidine-5-carboxylic acid (900 mg, 4.12 mmol) in CH3CN/DMF (10 mL/3 mL) was added HATU (1.73 g, 4.54 mmol), DIPEA (1.44 mL, 0.83 mmol) and cis-tert-butyl 3-amino-4-hydroxypyrrolidine-1-carboxylate (918 mg, 4.54 mmol). After 2 hrs, the solvents were removed in vacuo and the residue purified by chromatography (silica, 100% DCM to 5% MeOH/DCM) to give the desired product, cis-tert-butyl 3-(2-(3-fluorophenyl)pyrimidine-5-carboxamido)-4-hydroxypyrrolidine-1-carboxylate (2.33 g, 80%).