Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH:11]([N:13]([CH2:15][CH2:16][CH2:17][P:18](=[O:21])([OH:20])[OH:19])[OH:14])=[O:12].[OH-].[Na+]>CC(C)=O.O>[C:1]([O:14][N:13]([CH2:15][CH2:16][CH2:17][P:18](=[O:20])([OH:19])[OH:21])[CH:11]=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CN(O)CCCP(=O)(O)O
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=CN(CCCP(=O)(O)O)OC(=O)c1ccccc1
Reaction time: 0.17 h
Yield: 48.2 %

Procedure:
A solution of benzoyl chloride (700 mg) in dry acetone (6 ml) was added dropwise to a solution of sodium salt of 3-(N-formyl-N-hydroxyamino)propylphosphonic acid (820 mg) in a mixture of water (15 ml) and acetone (15 ml) under ice-cooling, while stirring. During this period, pH of the mixture was kept at around 7.5-7.7 with 1 N aqueous sodium hydroxide solution. The stirring was continued at the same temperature for 10 minutes and then acetone was evaporated under reduced pressure. The resulting aqueous solution was adjusted to pH 3.5 with 1N hydrochloric acid and ether (40 ml) was added thereto. After removal of the precipitated impurities, the aqueous layer was adjusted to pH 1.6 with 1N hydrochloric acid and extracted three times with ethyl acetate (50 ml, 20 ml×2). The combined ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness to give crystals, which were washed with ether to give crystalline 3-(N-benzoyloxy-N-formylamino)propylphosphonic acid (620 mg). Mp 149°-153° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:17]O)[C:11]([CH3:16])=[N:12][C:13]=2[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.[Cl:19]C1C=C(C2C(OC)=NC(C)=C(C=2)C=O)C=CC=1.[BH4-].[Na+]>CO>[Cl:19][CH2:17][C:10]1[C:11]([CH3:16])=[N:12][C:13]([O:14][CH3:15])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:9]=1
Reactant: COc1nc(C)c(C=O)cc1-c1cccc(Cl)c1
Reactant: COc1nc(C)c(CO)cc1-c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(C)c(CCl)cc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91 %

Procedure:
(5-(3-Chlorophenyl)-6-methoxy-2-methylpyridin-3-yl)methanol. To a solution of 5-(3-chlorophenyl)-6-methoxy-2-methylnicotinaldehyde (350 mg, 1.34 mmol) in methanol (3 mL) was added sodium borohydride (52 mg, 1.3 mmol). The solution was stirred at room temperature for 20 minutes then concentrated under reduced pressure. Purification (FCC, SiO2, 0-50%, EtOAc/hexanes) afforded the title compound (322 mg, 91%). [M+H]=264.06.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][NH2:29])[CH:22]=1>>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:29][CH2:28][CH2:27][C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=1
Reactant: NCCc1cccnc1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Product: COc1cc(CNCCc2cccnc2)ccc1Oc1ccc(C(N)=O)cn1
Yield: 58.3 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and 2-(pyridin-3-yl)ethylamine (0.0224 g, 0.184 mmol) gives the title compound (0.0406 g, 58.4%): TOF MS ES+ 379.2 (M+H)+, HRMS calcd for C21H23N4O3 379.1770 (M+H)+, found 379.1759, time 0.41 min.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C@@H:21]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:47][CH:46]=1)[C:22]([N:24]([CH2:36][CH:37]([O:41][CH2:42][CH3:43])[O:38][CH2:39][CH3:40])[CH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1)=[O:23]>>[CH2:1]([NH:8][C:9]([NH:11][N:12]([C:14]([CH3:19])([CH3:18])[C:15]([NH:20][C@@H:21]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][C:52]([CH3:54])([CH3:53])[CH3:55])=[CH:47][CH:46]=1)[C:22]([N:24]([CH2:36][CH:37]([O:41][CH2:42][CH3:43])[O:38][CH2:39][CH3:40])[CH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1)=[O:23])=[O:17])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CN(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)OCC
Reactant: CN(NC(=O)NCc1ccccc1)C(C)(C)C(=O)O
Product: CCOC(CN(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)C(C)(C)N(C)NC(=O)NCc1ccccc1)OCC
Yield: 58 %

Procedure:
According to the procedure described in the synthesis method of Compound II-1, 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)-2-methylpropanoic acid (Compound VI-5) (441 mg, 1.67 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N-(2,2-diethoxyethyl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-2) (544.6 mg, 1.11 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: chloroform:methanol=98:2) to obtain the title compound (476 mg, 58%).
Reaction SMILES: [N:1]([CH2:4][C:5]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2)([F:7])[F:6])=[N+]=[N-]>CO.[Pd]>[F:7][C:5]([F:6])([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2)[CH2:4][NH2:1]
Reactant: [N-]=[N+]=NCC(F)(F)c1cccc2cccnc12
Agent: [Pd]
Solvent: CO
Product: NCC(F)(F)c1cccc2cccnc12
Yield: 79.9 %

Procedure:
A solution of 8-(2-azido-1,1-difluoro-ethyl)-quinoline (3.8 g, 16.24 mmol) in MeOH (20 mL), as prepared in the last step, was treated with 10 wt. % Pd—C (754 mg) and NH4HCO2 (3 g). After 45 minutes the reaction was filtered through a pad of Celite and partitioned between EtOAc (100 mL) and NaHCO3 (satd) (100 mL). The organic phase was washed with brine (100 mL), dried over Na2SO4 and concentrated in vacuo to afford the product as a yellow viscous oil (2.7 g). 1H NMR (300 Hz, CDCl3) δ 9.0-8.98 (m, 1H), 8.22-8.19 (m, 1H), 8.05 (d, J=7.3 Hz, 1H), 7.93 (d, J=8.2 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.49-7.45 (m, 1H), 3.82 (t, J=15.3 Hz, 2H); LC/MS (m/z) [M+1]+ 209.2 (calculated for C11H10F2N2, 208.21).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:8]2[CH3:11])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[H-].[Na+].I[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>CN(C)C=O>[C:30]([O:29][C:28]([NH:27][CH2:26][CH2:25][CH2:24][O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:8]2[CH3:11])=[C:4]([C:17]([F:20])([F:18])[F:19])[CH:3]=1)=[O:34])([CH3:33])([CH3:32])[CH3:31]
Reactant: CCOC(=O)c1cc2c(C(F)(F)F)cc(O)cc2n1C
Reactant: CC(C)(C)OC(=O)NCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C(F)(F)F)cc(OCCCNC(=O)OC(C)(C)C)cc2n1C

Procedure:
The reaction was carried out in a manner similar to Reference Example 5 except for using 1.00 g (3.48 mmol) of ethyl 6-hydroxy-1-methyl-4-trifluoromethyl-2-indolecarboxylate, 0.14 g (3.48 mmol) of 60% sodium hydride, 0.99 g (3.48 mmol) of tert-butyl N-(3-iodopropyl)carbamate and 40 ml of dimethylformamide. Ethyl 6-(3-tert-butoxycarbonylaminopropoxy)-1-methyl-4-trifluoromethyl-2-indolecarboxylate was thus obtained in an amount of 1.28 g.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([O:14]C(=O)C)[CH:6]=1)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].O>C(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([OH:14])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc([N+](=O)[O-])c(OC(C)=O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1ccc([N+](=O)[O-])c(O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
To a solution of 4-nitro-1,3-phenylene diacetate (1.0 g) in chloroform (25 mL) was added aluminium chloride (2.23 g) with ice-cooling under nitrogen atmosphere. The reaction mixture was warmed to room temperature and stirred for 3 h. Then to the reaction mixture was added water (100 mL) and extracted with methylene chloride (30 mL×2). The combined organic layer was washed with 1N hydrochloric acid (25 mL) and saturated brine (25 mL) successively, dried over anhydrous sodium sulfate and was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using hexane/ethyl acetate (20:1) to give the title compound (610 mg).
Reaction SMILES: [NH2:1][C:2]([CH3:16])([CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([C:9]([Br:15])=[N:10][CH:11]=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[S:24])=[CH:21][CH:20]=1>>[Br:15][C:9]1[C:8]2=[N:7][N:6]([CH2:5][C:2]([NH:1][C:23](=[S:24])[C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:27][CH:26]=3)([C:3]#[N:4])[CH3:16])[CH:14]=[C:13]2[CH:12]=[CH:11][N:10]=1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CC(N)(C#N)Cn1cc2ccnc(Br)c2n1
Product: CC(C#N)(Cn1cc2ccnc(Br)c2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(7-bromo-2H-pyrazolo[3,4-c]pyridin-2-yl)-2-methylpropionitrile (100 mg, described in Example 202) and 4-trifluoromethylthiobenzoyl chloride (93 mg), the title compound was isolated as a white solid (153 mg, 89%). Rf=0.25 (1:1 EA/heptane). MS (ES): M/Z [M+H]=484. 1H NMR: (400 MHz, DMSO-d6): 1.70 (s, 3H), 5.18 (d, J=13.5 Hz, 1H), 5.33 (d, J=13.5 Hz, 1H), 7.76 (d, J=5.8 Hz, 1H), 7.87-7.90 (m, 3H), 7.96 (d, J=8.4 Hz, 1H), 8.71 (s 1H) and 9.01 (d, J=1.1 Hz, 1H). 19F NMR (376 MHz, DMSO-d6): −42.0 (s, 3F).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[N:5][NH:4][C:3]1=[S:13].I[CH3:15]>[OH-].[Na+].C(O)C>[CH3:1][N:2]1[C:3]([S:13][CH3:15])=[N:4][N:5]=[C:6]1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1
Reactant: CI
Reactant: Cn1c(-c2ccncc2)n[nH]c1=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1nnc(-c2ccncc2)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a solution of 4-Methyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione (1000 mg, 5.20 mmol) in 1M sodium hydroxide (10 mL), added a solution of iodomethane (0.52 mL, 8.32 mmol) in ethanol (3 mL). Stirred at RT overnight. Extracted into 200 mL dichloromethane and washed with brine (50 mL). Dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield title compound (1.00 g, 94% yield). 1H-NMR (CDCl3) δ (ppm): 8.81 (d, 2H), 7.62 (d, 2H), 3.68 (s, 3H), 2.82 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].[Na].[C:11]([O:15][CH2:16][CH:17]([OH:30])[CH2:18]OS(C1C=CC(C)=CC=1)(=O)=O)([CH3:14])([CH3:13])[CH3:12].[OH-].[Na+]>COCCO.O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:18][CH:17]([OH:30])[CH2:16][O:15][C:11]([CH3:14])([CH3:13])[CH3:12])#[N:2]
Reactant: N#Cc1ccccc1O
Reactant: Cc1ccc(S(=O)(=O)OCC(O)COC(C)(C)C)cc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: COCCO
Solvent: O
Product: CC(C)(C)OCC(O)COc1ccccc1C#N
Reaction time: 0.08 h

Procedure:
o-Cyanophenol (5.95 g.) is added to a solution of sodium (1.15 g.) in 2-methoxyethanol (20 ml.), the mixture is stirred for 5 minutes, and a solution of 3-t-butoxy-1-toluene-p-sulphonyloxypropan-2-ol (15.1 g.) in 2-methoxyethanol (30 ml.) is added. The mixture is heated under reflux for 90 minutes, cooled and poured into a mixture of ice and water (150 ml.), and the mixture is basified with aqueous 2 N-sodium hydroxide solution and extracted twice with chloroform (100 ml. each time). The combined extracts are washed with water, dried and evaporated to dryness and the residue is chromatographed on a slica gel column using chloroform as eluant. The appropriate fractions of the eluate are evaporated to dryness and there is thus obtained as oily residue 1-o-cyanophenoxy-3-t-butoxypropan-2-ol, the structure of which is confirmed by proton magnetic resonance spectroscopy.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]2[N:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C:3]1=[O:17].CN(C=O)C.[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[CH2:25]([N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3](=[O:17])[C:4]2[CH:16]=[CH:15][CH:14]=[N:13][C:5]1=2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN1C(=O)c2cccnc2Nc2ccccc21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CN1C(=O)c2cccnc2N(Cc2ccccc2)c2ccccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To a mixture of 4.0 g of 6,11-dihydro-6-methyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 100 ml of dry DMF was added 1.2 g of 50% NaH in mineral oil. The resulting solution was heated to 60° C. for one hour. The dark red solution was cooled to 30° C. and 2.5 ml of benzyl bromide was added and stirred overnight under nitrogen. Methanol was added slowly until bubbling ceased, and the reaction mixture was then poured into 400 ml of water. The product was extracted with ether, dried over MgSO4, then concentrated and purified by column chromatography over silica gel. Elution of the material with 2% ethyl acetate/methylene chloride gave a white solid, which was recrystallized from methylene chloride/ether/petroleum ether to give 2.2 g (39% of theory) of 6,11-dihydro-11-benzyl-6-methyl-5H-pyrido[2,3-b][1,5]benzodiazapin-5-one, m.p. 168°-170° C.
Reaction SMILES: [Na].[OH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]([OH:15])=[O:14].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>CS(C)=O>[OH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]([O:15][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)=[O:14]
Reactant: COc1ccc(CCl)cc1
Reactant: O=C(O)c1ccc2ccccc2c1O
Agent: [Na]
Solvent: CS(C)=O
Product: COc1ccc(COC(=O)c2ccc3ccccc3c2O)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 66431.7 %

Procedure:
(This is a compound 15a of Scheme 1). A suspension of powdered sodium salt of 1-hydroxynaphthalene-2-carboxylic acid (1) (61.3 g, 0.29 mmol) in DMSO (205 mL) was treated with 4-methoxybenzyl chloride (98%, 46.7 g, 0.29 mmol) and then stirred at 70° C. for 1 h. After cooling, the mixture was poured into dilute aqueous KHCO3 (3.5 L) and the resulting precipitate was collected, washed with water and dried. The solid was extracted with boiling petroleum ether (bp 60-65° C., 1100 mL), treated with decolourising charcoal and the filtered solution was cooled for a prolonged period at 0° C. to provide crude 4-methoxybenzyl 1-hydroxynaphthalene-2-carboxylate (2) (59.4 g, 66%), suitable for further use. A sample was recrystallised from iPr2O/petroleum ether, mp 92-93° C. 1H NMR [(CD3)2SO] δ 11.91 (s, 1H, OH), 8.31 (d, J=8.2 Hz, 1H, H-3), 7.92 (d, J=8.1 Hz, 1H, H-4), 7.73 (d, J=8.8 Hz, 1H, ArH), 7.71 (brt, J=7.5 Hz, 1H, ArH), 7.61 (br t, J=1.6 Hz, 1H, ArH), 6.99 (d, J=8.6 Hz, 2H, H-3',5'), 5.40 (s, 2H, CH2), 3.34 (s, 3H, CH3). Anal. Calculated for C19H16O4): C, 74.0; H, 5.2. Found: C, 73.7; H, 5.2%.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][CH:14]([C:23]1[CH:24]=[CH:25][C:26](=[O:30])[N:27]([CH3:29])[CH:28]=1)[N:15]1[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17][CH2:16]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:12][CH2:13][CH:14]([N:15]1[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17][CH2:16]1)[C:23]1[CH:24]=[CH:25][C:26](=[O:30])[N:27]([CH3:29])[CH:28]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: Cn1cc(C(CN)N2CCC(F)(F)CC2)ccc1=O
Product: Cn1cc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CCC(F)(F)CC2)ccc1=O

Procedure:
From 2,3-dichlorobenzoic acid and 5-(2-amino-1-(4,4-difluoropiperidin-1-yl)ethyl)-1-methylpyridin-2(1H)-one.
Reaction SMILES: CN([CH:4]=[C:5]1[CH2:11][C:10](=[O:12])[NH:9][C:8]2[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:7]=2[C:6]1=O)C.[NH:19]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)[C:20]([NH2:22])=[NH:21]>>[F:17][C:15]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[CH2:11][C:5]3[CH:4]=[N:22][C:20]([NH:19][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)=[N:21][C:6]=3[C:7]=2[CH:16]=1
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Reactant: CN(C)C=C1CC(=O)Nc2ccc(F)cc2C1=O
Product: O=C1Cc2cnc(Nc3ccc(C(=O)O)cc3)nc2-c2cc(F)ccc2N1

Procedure:
In a manner similar to that described for Method H, 4-dimethylaminomethylene-7-fluoro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-f) and 4-guanidinobenzoic acid were converted to I-5 (98%): HRMS Calcd. for C19H13FN4O3: 365.1049, Found 365.1069.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])=[C:8]([CH:17]=1)[O:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)([O-:3])=[O:2].[CH3:25][C:26]([CH3:28])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCCl>[CH:26]([N:14]1[CH2:15][CH2:16][CH:11]([CH2:10][O:9][C:8]2[CH:17]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[C:18]([F:24])([F:23])[C:19]([F:20])([F:21])[F:22])[CH2:12][CH2:13]1)([CH3:28])[CH3:25]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(OCC2CCNCC2)c1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)N1CCC(COc2cc([N+](=O)[O-])ccc2C(F)(F)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolved 4-(5-nitro-2-pentafluoroethyl-phenoxymethyl)-piperidine (646 mg) in DCE(6.4 mL), then added acetone (136 μl), NaBH(OAc)3 (541 mg) and finally acetic acid (105 μL). Stirred the cloudy yellow solution under N2 at RT overnight. Added another 130 μL acetone and stirred at RT over weekend. Quenched the reaction with 30 mL N NaOH/H2O and stirred 10 min. Extracted with Et2O and the organic layer was brine-washed, dried over Na2SO4, filtered and concentrated in vacuo. Dried under high vacuum for several h to obtain 1-isopropyl-4-(5-nitro-2-pentafluoroethyl-phenoxymethyl)-piperidine as a yellow orange solid.
Reaction SMILES: [CH2:1]([C:4]1[C:12]([OH:13])=[CH:11][C:10]([CH3:14])=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)[CH:2]=[CH2:3].CO.[C:17](C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH2:1]([C:4]1[C:12]([O:13][CH3:17])=[CH:11][C:10]([CH3:14])=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)cc(C)c2[nH]ccc12
Reactant: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CO
Product: C=CCc1c(OC)cc(C)c2[nH]ccc12
Temperature: 110 °C

Procedure:
4-Allyl-7-methyl-1H-indol-5-ol (Example 1-C) (2.77 g, 14.79 mmol) was dissolved in toluene (74.0 mL) and methanol (0.599 mL, 14.79 mmol) was added followed by cyanomethylenetributylphosphorane (8.93 g, 37.0 mmol). The reaction was heated at 110° C. for 1 hour. The reaction was cooled to room temperature and then concentrated. The residue was then absorbed onto silica and purified by silica gel flash chromatography (0-50% ethyl acetate/heptanes) to provide the title compound. MS (ESI+) m/z 202.17 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@:9]([CH:12]([O:15][CH3:16])[O:13][CH3:14])([CH3:11])[C@H:8]([OH:17])[C@@H:7]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][C:19]3=[S:27])[C:6]=2[CH:28]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH3:29][S:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@:9]([CH:12]([O:15][CH3:16])[O:13][CH3:14])([CH3:11])[C@H:8]([OH:17])[C@@H:7]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][C:19]3=[S:27])[C:6]=2[CH:28]=1)(=[O:32])=[O:31]
Reactant: COC(OC)[C@]1(C)Oc2ccc(N)cc2[C@H](n2c(=S)oc3ccccc32)[C@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COC(OC)[C@]1(C)Oc2ccc(NS(C)(=O)=O)cc2[C@H](n2c(=S)oc3ccccc32)[C@H]1O
Temperature: 25 °C
Reaction time: 10 h
Yield: 63.4 %

Procedure:
90 mg (0.22 mmol) of the compound prepared in Example 17 was dissolved in 1 ml of dichloromethane, to which 58 μl (0.34 mmol) of methanesulfonyl chloride and 17 μl (0.22 mmol) of diaisopropylethylamine were added. The reaction was stirred for 10 hours at room temperature, 67 mg (yield: 64%) of the target compound was obtained through reaction accomplished by the same procedure as used in Example 33.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.C([Sn](CCCC)(CCCC)[C:24]1[S:25][CH:26]=[CH:27][N:28]=1)CCC.O>O1CCOCC1>[S:25]1[CH:26]=[CH:27][N:28]=[C:24]1[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(-c2nc3ncccn3c2Br)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2nc3ncccn3c2-c2nccs2)cc1
Temperature: 100 °C

Procedure:
0.5 g (1.65 mM) 4-(3-bromoimidazo[1,2-a]pyrimidin-2-yl)benzaldehyde is dissolved in 15 mL of 1,4-Dioxane. To this solution is added tetrakis triphenylphosphine palladium (200 mg) 40%. The reaction mixture is heated at 100° C. for 10 min. and 2-(tributylstannyl)-1,3-thiazole is added (681 mg, 1.81 mM). The reaction is heated (oil bath or microwave) at same temp for 5 h. The reaction is cooled to room temperature and 50 mL of water is added and the reaction mixture is extracted with ethyl acetate. The organic layer is dried and concentrated. The crude is purified by flash column chromatography to yield the desired product.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:15][CH:14]([O:16][C:17]2[C:18]([C:23]3[CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][CH2:27][CH:28]=3)=[N:19][CH:20]=[CH:21][N:22]=2)[CH2:13]1)=[O:11].FC(F)(F)C(O)=O>C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:13][CH:14]([O:16][C:17]2[C:18]([C:23]3[CH2:24][NH:25][CH2:26][CH2:27][CH:28]=3)=[N:19][CH:20]=[CH:21][N:22]=2)[CH2:15]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC=C(c2nccnc2OC2CN(C(=O)c3nc4ccccc4[nH]3)C2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1nc2ccccc2[nH]1)N1CC(Oc2nccnc2C2=CCCNC2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butyl 3-(3-(1-(1H-benzo[d]imidazole-2-carbonyl)azetidin-3-yloxy)pyrazin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (see EXAMPLE 10.72; 120 mg, 0.252 mmol) in DCM (2 mL) is added 2,2,2-trifluoroacetic acid (116 μL, 1.511 mmol). The reaction was stirred at room temperature 24 hours. The reaction was concentrated, and the residue dissolved in MeOH (2 mL) and applied to a Varian SCX ion exchange column (1 g). The salt was eluted with MeOH (2×5 mL) and the product eluted with 2.0 M NH3 in MeOH (2×5 mL). The NH3 containing fractions were concentrated to give the crude amine which was carried on to the next step without further purification.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3](=O)[O:2]1.[Br:12][C:13]1[CH:14]=[C:15]([CH2:20]C(O)=O)[CH:16]=[CH:17][C:18]=1[F:19].C([O-])(=O)C.[Na+]>>[Br:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:18]=1[F:19])[CH:20]=[C:3]1[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[C:1](=[O:11])[O:2]1
Reactant: O=C(O)Cc1ccc(F)c(Br)c1
Reactant: O=C1OC(=O)C2=C1CCCC2
Agent: CC(=O)[O-]
Agent: [Na+]
Product: O=C1OC(=Cc2ccc(F)c(Br)c2)C2=C1CCCC2

Procedure:
4,5,6,7-tetrahydro-isobenzofuran-1,3-dione (7) (16.7 g, 109.7 mmol) and 3-bromo-4-fluorophenylacetic acid (15.0 g, 64.37 mmol) were heated in the presence of sodium acetate (0.259 g, 3.160 mmol) to 210° C. using a ‘Wood's Alloy’ bath for 4.5 hours. The reaction mixture was then poured into a crucible and cooled to give a crystalline solid. The solid was ground with a mortar and pestle and triturated with ethanol (20 ml). The resultant suspension was then filtered and washed with further ethanol (10 ml). The solid was then dried to afford the desired product as a mixture of geometric isomers. Main peak in LC-MS, (20.78 g, 94% purity) and required no further purification; m/z (LC-MS, ESP), RT=4.74 mins (no ionization observed).