Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:13]([O:8][C:6]1[CH:5]=[CH:4][C:3]([C:9](=[O:12])[CH2:10][CH3:11])=[C:2]([OH:1])[CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: CCC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(=O)c1ccc(OCc2ccccc2)cc1O
Yield: 60.9 %

Procedure:
A mixture of 5.0 g of 2',4'-dihydroxypropiophenone, 5.4 g of benzyl bromide, 6.2 g of potassium carbonate and 50 ml of acetone was refluxed for 7 hours. After cooling, the solid was separated by filtration. The filtrate was concentrated, and the residue was separated by column chromatography to give 4.7 g of 4'-benzyloxy-2'-hydroxypropiophenone as a white solid (yield 61%, melting point 111.5°-112.5° C.). Then, a mixture of 4.5 g of this solid, 3.5 g of ethyl bromoacetate, 6.1 g of potassium carbonate and 45 ml of acetone was refluxed for 7.5 hours. After cooling, the solid was separated by filtration. The filtrate was concentrated, and the residue was purified by column chromatography to give 5.8 g of ethyl 3-benzyloxy-6-propionylphenoxyacetate as white crystals (yield 97%, melting point 81.5° to 82.0° C.). This ester (5.5 g) was dissolved in a solution composed of 1.3 g of potassium hydroxide and 55 ml of methanol, and the solution was stirred at room temperature for 2 hours to hydrolyze the ester. The hydrolysis product was worked up in a customary manner to give 3.9 g (yield 77%) of 3-benzyloxy-6-propionylphenoxyacetic acid as a pale yellowish orange solid. Then, 9.3 g of sodium acetate and 39 ml of acetic anhydride were added to this solid, and the mixture was heated at 155° C. for 30 minutes. The solvent was evaporated, and the residue was purified by column chromatography to give 2.8 g (yield 95%, melting point 69.5°-70.5° C.) of 6-benzyloxy-3-ethylbenzofuran as a white solid. Palladium (5%)-carbon (0.27 g) and 27 ml of acetic acid were added to 2.7 g of the resulting benzofuran, and the mixture was stirred at room temperature for 3 hours in an atmosphere of nitrogen. The catalyst was separated by filtration, and the filtrate was concentrated and then purified by column chromatography to give 1.7 g (yield 90%) of the desired product as a pale orange liquid.
Reaction SMILES: [F-:1].[F:2][C:3]([F:14])([C:11](Cl)=[O:12])[O:4][C:5]([F:10])([F:9])[C:6](Cl)=[O:7].[F-:15].[Na+]>C(#N)C>[F:2][C:3]([F:14])([C:11]([F:15])=[O:12])[O:4][C:5]([F:10])([F:9])[C:6]([F:1])=[O:7]
Reactant: O=C(Cl)C(F)(F)OC(F)(F)C(=O)Cl
Reactant: [F-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(F)C(F)(F)OC(F)(F)C(=O)F
Reaction time: 8 h

Procedure:
Conversion of the diacid chloride to the corresponding fluoride, bp 32°-33° C., was accomplished by a scale-up of the procedure of R. E. Banks, E. D. Burling, B. A. Dodd, and K. Mullen, J. Chem. Soc. (c), 1706 (1969). A mixture of 215 g (0.885 mol) of tetrafluorodiglycolyl dichloride, 140.5 g (3.35 mol) of NaF, and 1200 ml of anhydrous acetonitrile was stirred overnight, then distilled to give a fraction collected at 35°-79° C. The distillate was treated with 20 g of NaF and distilled to give 105 g of tetrafluorodiglycolyl difluoride, bp 32°-33° C. Addition of another 100 g (2.38 mol) of NaF to the reaction mixture and slow distillation afforded another fraction, bp 35°-81° C. Treatment with 10 g of NaF and fractionation gave another 37.0 g of difluoride product, bp 32°-33° C., for a total of 142 g (76%).
Reaction SMILES: [Br-].C1(=O)[N:6]([CH2:7][C:8]2[CH:33]=[CH:32][C:11]([CH2:12][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:10][CH:9]=2)[C:5](=[O:34])[C:4]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:3]12.[CH3:40][O-:41].[Na+].[C:43]([C:45]1[CH:52]=[CH:51][C:48]([CH:49]=O)=[CH:47][CH:46]=1)#[N:44]>CO>[C:5]1(=[O:34])[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH:12]=[CH:49][C:48]3[CH:51]=[CH:52][C:45]([C:43]#[N:44])=[CH:46][CH:47]=3)=[CH:32][CH:33]=2)[C:40](=[O:41])[C:35]2=[CH:36][CH:37]=[CH:38][CH:3]=[C:4]12
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: C[O-]
Reactant: N#Cc1ccc(C=O)cc1
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(C=Cc2ccc(CN3C(=O)c4ccccc4C3=O)cc2)cc1
Reaction time: 0.08 h

Procedure:
Into 800 ml of anhydrous methanol, was dissolved 35.5 g of 4-phthalimidomethylbenzyltriphenylphosphonium bromide. To the resulting solution, through which argon had been passed with stirring for 5 minutes, was added at room temperature slowly dropwise 11.6 ml of anhydrous methanol containing 28% of sodium methoxide. After 10 minutes, 7.9 g of p-cyanobenzaldehyde was added to the reaction mixture and the mixture was stirred at room temperature for 15 hours. The precipitated crystals were collected by filtration to obtain 15.4 g of 4-[2-(4-phthalimidomethylphenyl)ethenyl]benzonitrile.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]CO)=[N+:2]=[N-:3].S(Cl)(C)(=O)=O.[CH3:16][S:17]([O:20][CH2:21]CN=[N+]=[N-])(=[O:19])=[O:18]>>[CH3:16][S:17]([O:20][CH2:21][CH:4]([N:1]=[N+:2]=[N-:3])[CH2:5][CH2:6][CH2:7][CH3:8])(=[O:19])=[O:18]
Reactant: [N-]=[N+]=NCCCCCCO
Reactant: CS(=O)(=O)OCCN=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Product: CCCCC(COS(C)(=O)=O)N=[N+]=[N-]

Procedure:
Reaction of 6-azidohexanol (0.74 g, 5.22 mmol) and mesyl chloride (0.61 mL, 7.83 mmol) within 3 h as described for synthesis of 156a gave compound 156e (0.87 g) as a crude colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[CH:4][N:3]=1.[CH3:14][CH2:15][Mg+].[Br-]>C1COCC1>[OH:1][C:2]1[N:3]=[CH:4][C:5]([C:6](=[O:7])[CH2:14][CH3:15])=[CH:12][CH:13]=1
Reactant: CON(C)C(=O)c1ccc(O)nc1
Reactant: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(O)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
To a solution of 6-hydroxy-N-methoxy-N-methylnicotinamide (800 mg, 1.0 eq) in 20 mL anhydrous THF was added 3 M EtMgBr (6 mL, 4.0 eq) dropwise at 0° C. The reaction mixture was stirred at rt for 2 h., quenched with sat NH4Cl, and extracted with CH2Cl2. The extract was dried, concentrated, and purified by column chromatography to give the desired product (320 mg, 48%). 1H NMR (400 MHz, CDCl3) δ 12.13 (brs, 1H), 8.11 (d, J=2.4 Hz, 1H), 8.05 (dd, J=10.0 Hz, 2.8 Hz, 1H), 6.60 (d, J=9.6 Hz, 1H), 2.79 (q, J=7.2 Hz, 2H), 1.22 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1](=[CH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[C:18]([CH2:21][N+]1C=CC=CC=1)(=[O:20])[NH2:19].[OH-].[Na+]>CO.O>[C:11]1([C:9]2[CH:8]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[NH:19][C:18](=[O:20])[CH:21]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Reactant: NC(=O)C[n+]1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=c1cc(-c2ccccc2)cc(-c2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of benzylideneacetophenone (41.6 g) and N-carbamoylmethylpyridinium chloride (34.4 g) (prepared according to the method of O. ALBRECHT et al., Helv. Chim. Acta 24, 241E (1941)) in methanol (600 cc), is added, at room temperature, a 1N aqueous solution of sodium hydroxide (200 cc). The initially yellow solution takes on an orange colour and a yellow solid precipitates. The mixture is stirred at room temperature for 15 minutes and acetic acid (400 cc) is then added. The green solution obtained is stirred for 1 hour at room temperature. The solvent is then distilled in 4 hours under atmospheric pressure. The solid residue obtained is taken up in distilled water (500 cc). After stirring for 1 hour at more temperature, the solid is separated by filtration, washed with distilled water (3×100 cc) and dried under reduced pressure at 60° C. (whitish solid; m.p.=209°-212° C.)
Reaction SMILES: [CH2:1]1[O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:13][CH:14]([CH2:17][CH2:18][NH2:19])[CH2:15][NH2:16]>>[CH3:13][CH:14]([CH2:17][CH2:18][NH:19][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:15][NH:16][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCC1CO1
Reactant: CC(CN)CCN
Product: CCCCCCCCCC(O)CNCCC(C)CNCC(O)CCCCCCCCC

Procedure:
Condensation of 1-undecene oxide and 2-methyl-1,4-butanediamine affords N,N'-(2-methyl-1,4-butylene)-bis[2-hydroxyundecylamine] (I: R= CH3 (CH2)8, R' = H, X= CH2CH(CH3)CH2CH2, Z= H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[F:10][C:11]([F:24])([O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O)[CH:12]([F:14])[F:13]>C1CCCCC1>[F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH:4][CH2:19][C:18]1[CH:21]=[CH:22][CH:23]=[C:16]([O:15][C:11]([F:10])([F:24])[CH:12]([F:13])[F:14])[CH:17]=1
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: Nc1cc(F)ccc1F
Solvent: C1CCCCC1
Product: Fc1ccc(F)c(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Temperature: 0 °C
Yield: 85 %

Procedure:
EX-661A) A mixture of 2.5-difluoroaniline (2.58 g, 20 mmol) and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (4.44 g, 20 mmol) in cyclohexane (50 mL) was heated under reflux for 5 h using a Dean-Stark trap to remove water. The solvent was removed in vacuo, and the residue was dissolved in methanol (30 mL). The solution was stirred and cooled to 0° C., then sodium borohydride was added (1.32 g, 35 mmol). The mixture was allowed to warm to room temperature and stirred for 2 h, then acidified with 1 N HCl. After neutralizing to pH 7.5 with 2.5 N sodium hydroxide, the mixture was extracted with diethyl ether (3×20 mL). The organic layer was washed with brine and water, then dried over anhydrous MgSO4, and evaporated to give 5.7 g (86%) of the desired N-(2,5-difluorophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amine product as a brown oil, which was greater than 90% pure by reverse phase HPLC analysis. MS m/z=336 [M+].
Reaction SMILES: CS(C)=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.[OH-].[K+].Cl[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24]>O>[N+:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:13][C:9]1[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=[CH:11][CH:10]=1)([O-:25])=[O:24]
Reactant: COc1cccc(O)c1
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1cccc(Oc2ccccc2[N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 97.1 %

Procedure:
To 150 ml of dimethyl sulfoxide were added 19.9 g of 3-methoxyphenol and 9.1 g of potassium hydroxide and the mixture was heated to 70°-80° C. to prepare a homogeneous solution. To this solution was added 21.1 g of 2-chloronitrobenzene and the mixture was stirred at 100° C. for 4 hours. The reaction mixture was then diluted with water and extracted with ether and the ether extract was washed succesively with 10% sodium hydroxide solution and saturated sodium chloride solution. The washed extract was dried over magnesium sulfate and the ether was distilled off to give 31.9 g of the title compound as a light yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].C([O:15][CH2:16][CH:17]1[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18]1)(=O)C1C=CC=CC=1>O>[CH3:22][C:19]1([CH3:23])[O:18][CH:17]([CH2:16][OH:15])[CH2:21][O:20]1
Reactant: CC1(C)OCC(COC(=O)c2ccccc2)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC1(C)OCC(CO)O1
Temperature: 100 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
Sodium carbonate (16.53 g, 0.156 mol) was added to a mixture of the crude 4-benzoyloxymethyl-2,2-dimethyl-1,3-dioxolane (24.63 g, 0.104 mol) and water (50 ml) and resulting mixture was stirred for 8 hours at 100° C. After cooling the mixture was extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and condensed in vacuo. The residue was distilled to give 10.86 g of 2,2-dimethyl-1,3-dioxolane-4-methanol (yield 79%, b.p. 68° C. at 6 mmHg).
Reaction SMILES: [CH2:1]([S:3]([NH:6][CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:5])=[O:4])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[I:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br>CN(C)C=O.C(OCC)(=O)C>[I:20][C:21]1[CH:22]=[C:23]([CH2:24][N:6]([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:26]=[CH:27][CH:28]=1
Reactant: BrCc1cccc(I)c1
Reactant: CCS(=O)(=O)NCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N(Cc1cccnc1)Cc1cccc(I)c1

Procedure:
A solution of N-(ethylsulfonyl)pyrid-3-ylmethylamine (1.1 g, 5.5 mmol), cesium carbonate (1.79 g, 5.5 mmol), and 3-iodobenzyl bromide (1.64 g, 5.5 mmol) was stirred in N,N-dimethylformamide (25 ml) for 5 h at room temperature. The mixture was diluted with ethyl acetate (100 ml) and washed four times with water (50 ml). The organics were separated, dried over sodium sulfate, filtered, and concentrated in vacuo to a crude residue. The residue was purified by radial chromatography on a 4 micron silica plate eluting with 3% methanol/dichloromethane to afford the title compound. 1H NMR: 8.6 (d,1H,J=4 Hz), 8.41 (s,1H), 7.75 (m,1H), 7.65 (m,1H), 7.60 (s,1H), 7.25-7.40 (m,2H), 7.08 (m,1H), 4.43 (s,2H), 4.33 (s,2H), 3.08 (q,2H,J=8 Hz), 1.43 (t,3H,J=8 Hz). MS calcd. 416.3; MS (M+1) 417.1.
Reaction SMILES: [Cl-].[C:2]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([NH:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH+:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=3)[CH2:15][CH2:14]2)=[O:10])=[CH:7][CH:6]=1)([OH:4])=O.[Br:31][C:32]1[C:40]2OC(C3C=CC(C([O-])=O)=CC=3)=[N:37][C:36]=2[CH:35]=[C:34]([C:50]#[N:51])[CH:33]=1>>[Br:31][C:32]1[C:40]2[O:4][C:2]([C:5]3[CH:30]=[CH:29][C:8]([C:9]([NH:11][CH2:12][CH:13]4[CH2:18][CH2:17][N:16]([C:19]5[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][N:20]=5)[CH2:15][CH2:14]4)=[O:10])=[CH:7][CH:6]=3)=[N:37][C:36]=2[CH:35]=[C:34]([C:50]#[N:51])[CH:33]=1
Reactant: O=C(O)c1ccc(C(=O)NCC2CC[NH+](c3ccc(C(F)(F)F)cn3)CC2)cc1
Reactant: N#Cc1cc(Br)c2oc(-c3ccc(C(=O)[O-])cc3)nc2c1
Agent: [Cl-]
Product: N#Cc1cc(Br)c2oc(-c3ccc(C(=O)NCC4CCN(c5ccc(C(F)(F)F)cn5)CC4)cc3)nc2c1

Procedure:
The title compound was prepared from 4-{[(4-carboxybenzoyl)amino]methyl}-1-[5-(trifluoromethyl)pyridin-2-yl]piperidinium chloride and 3-amino-5-bromo-4-hydroxybenzonitrile (INTERMEDIATE 1, Step B) by a procedure analogous to that described in EXAMPLE 109. Mass spectrum (ESI) 585.9 (M+3).
Reaction SMILES: N[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[C:13]1(=[O:23])[O:18][C:16](=O)[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.O.[C:25]1(C)C=CC=CC=1>>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][CH:25]2[C:13](=[O:23])[C:14]3[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16]2=[O:18])=[CH:5]1
Reactant: Cc1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCc1c[nH]c2ccccc12
Solvent: O
Product: O=C1c2ccccc2C(=O)C1CCc1c[nH]c2ccccc12
Yield: 90 %

Procedure:
Tryptamine (3.09 g; 19 mmol) was dissolved in toluol (300 ml). Phthalic anhydride (3 g; 20.2 mmol) was then added. The yellow reaction solution was boiled with reflux for 7 h (water separator). The course of the reaction was controlled by DC. For work up toluol was distilled off completely. The remaining yellow solid was recrystallised from cyclohexane/chloroform (1:1). 4.796 g (90%) of the product were obtained.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].[C:13]1([C@@H:19]2[C@@H:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:22][C:21]3([CH2:34][CH2:33][CH2:32][C@H:31]([CH2:35][NH2:36])[CH2:30]3)[O:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>C(#N)C.CO>[C:13]1([C@@H:19]2[C@@H:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:22][C:21]3([CH2:34][CH2:33][CH2:32][C@H:31]([CH2:35][NH:36][C:2]4[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=4[N+:10]([O-:12])=[O:11])[C:5]#[N:6])[CH2:30]3)[O:20]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NC[C@H]1CCCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2
Reactant: N#Cc1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Solvent: CO
Product: N#Cc1ccc([N+](=O)[O-])c(NC[C@H]2CCCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 88 %

Procedure:
A mixture of 3-fluoro-4-nitrobenzonitrile (55.5 g, 334 mmol), 1-[(2R,3R,7S)-2,3-diphenyl-1,4dioxaspiro[4.5]dec-7-yl]methanamine (103 g, 318 mmol) and potassium carbonate (88 g, 637 mmol) in acetonitrile (2654 mL) was stirred at RT for 5 days (˜200 mL DCM was added to help with solubility). The resulting solution was filtered and the solids washed with MeCN. The resulting solution was concentrated to give the crude product that was dissolved in MeOH (500 mL) and allowed to crystallize with stirring. The slurry was allowed to stir at RT overnight, filtered and the solids dried under reduced pressure to give 3-({[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4.5]dec-7-yl]methyl}amino)-4-nitrobenzonitrile (131.41 g, 88% yield). The product was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[CH:28]=[C:29]([CH:46]=[CH:47][C:48]=1[F:49])[O:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([N:37]=[C:38]([NH:40][C:41]([CH:43]3[CH2:45][CH2:44]3)=[O:42])[N:39]=2)[CH:36]=1>CN(C)C=O.CN(C)C(=O)C>[CH:43]1([C:41]([NH:40][C:38]2[N:39]=[C:34]3[CH:33]=[CH:32][C:31]([O:30][C:29]4[CH:46]=[CH:47][C:48]([F:49])=[C:27]([NH:26][C:7]([C:5]5[N:4]([CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]=[C:2]([CH3:1])[CH:6]=5)=[O:9])[CH:28]=4)=[CH:36][N:35]3[N:37]=2)=[O:42])[CH2:44][CH2:45]1
Reactant: Cc1cc(C(=O)O)n(CC(F)(F)F)n1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)ccc2F)n(CC(F)(F)F)n1
Yield: 83.5 %

Procedure:
In the same manner as in Example 18-4 and using 3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxylic acid (254 mg, 1.22 mmol), tetrahydrofuran (7 mL), oxalyl chloride (160 μL, 1.83 mmol), N-[6-(3-amino-4-fluorophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.611 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (264 mg, 84%) was obtained as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:7].N1C=CN=C1.[Si:19](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O.O>[Si:19]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C(CCCCO)c1cccnc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCCCC(=O)c1cccnc1)(c1ccccc1)c1ccccc1

Procedure:
A solution of 4.59 g (0.0256 mole) of 5-hydroxy-1-(3-pyridyl)pentan-1-one, 3.82 g (0.0561 mole) of imidazole 7.76 g (0.0282 mole) of tert-butyldiphenylsilylchloride in 10 ml of dimethylformamide is stirred at room temperature for 15 h, diluted with 75 ml of water and extracted with ethyl acetate (2×50 ml). The extracts are washed with water and brine, dried (MgSO4) and evaporated. The residue is purified by flash chromatography using methylene chloride-ethyl acetate (4:1) as eluent to give 5-(t-butyldiphenylsilyloxy)-1-(3-pyridyl)pentan-1-one as an oil.
Reaction SMILES: [CH:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[NH:21][C:20]3=[S:28])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[H-].[Na+].[CH3:31]I.O>CN(C=O)C>[CH:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]([CH3:31])[C:20]3=[S:28])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: CI
Reactant: S=c1[nH]c2ccccc2n1C1CCN(C2Cc3cccc4cccc2c34)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=S)n(C2CCN(C3Cc4cccc5cccc3c45)CC2)c2ccccc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 101.1 %

Procedure:
(RS)-1-[1-(Acenaphthen-1-yl)piperidin-4-yl]-1,3-dihydro-2H-benzoimidazole-2-thione (1 g, 2.6 mmol) was dissolved in DMF (15 ml) and sodium hydride (120 mg, 60%) was added. The suspension was stirred at 50° C. for 30 min. After cooling to room temperature, methyl iodide (0.4 g, 2.8 mmol) was added and the mixture was stirred for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated aqueous ammonium chloride solution, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (1.05 g) as pale-yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.Cl[C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1>[Cl:28][C:27]1[C:22]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]3)=[CH:4][CH:3]=2)=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)cc2)C1
Reactant: Clc1cccnc1Cl
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Nc3ncccc3Cl)cc2)C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
(S)-tert-Butyl 2-(4-aminophenyl)morpholine-4-carboxylate (120 mg, 0.43 mol), 2,3-dichloropyridine (64 mg, 0.43 mmol) and cesium carbonate (211 mg, 0.647 mmol) were combined with dioxane (2 ml) to give a suspension. The mixture was degassed with argon for 5 min. Xanthphos (15 mg, 0.026 mmol) and tris(dibenzylideneacetone)dipalladium chloroform complex (13 mg, 0.013 mmol) were added. The reaction mixture was capped and stirred at 100° C. for 2 h. The crude reaction mixture was filtered through a syringe filter, concentrated in vacuo and purified by flash chromatography (20 g silica gel, 5 to 20% ethyl acetate in heptane) yielded a light yellow foam (88 mg, 53%); MS (ISP): 390.2 ([{35Cl}M+H]+), 392.2 ([{37Cl}M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[CH3:20][O:21][CH2:22][C:23](OC)=[O:24].Cl>C(OCC)C>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:23](=[O:24])[CH2:22][O:21][CH3:20])=[CH:6][CH:7]=1
Reactant: Brc1ccc(Br)nc1
Reactant: COCC(=O)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COCC(=O)c1ccc(Br)nc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 32.6 %

Procedure:
To a suspension of 2,5-dibromopyridine (50.0 g) in diethyl ether (1 L) was added under nitrogen atmosphere a 1.6M n-butyllithium hexane solution (140 mL) at −70° C. over 20 min. The reaction mixture was stirred at −70° C. for 30 min, methyl methoxyacetate (44.0 g) was added at −70 to −45° C. over 15 min. The reaction mixture was warmed to room temperature, 2M hydrochloric acid (110 mL) was added, and the diethyl ether layer was separated. The aqueous layer was extracted with ethyl acetate, the ethyl acetate layer was combined with the diethyl ether layer, and the layers were washed with saturated brine, dried (MgSO4) and concentrated. Cold ether was added to the obtained residue, and the resulting crystals were collected by filtration, washed with cold ether and dried to give the title compound (15.85 g, yield 33%) as colorless crystals. melting point 110-112° C.