Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[Cl:9]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>C(Cl)(Cl)Cl.C(N)(=O)C1C=CC=CC=1>[Cl:9][CH2:1][C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: Cc1nccnc1Cl
Agent: NC(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: ClCc1nccnc1Cl
Yield: 43.7 %

Procedure:
Prepare the title compound using the chlorination procedure as essentially described by Jeromin, G. E.; et al., DE3519364, 1986, and Russell, M. G. N.; et al. J. Med. Chem. 2005, 48, 1367-1383. Dissolve 2-methyl-3-chloropyrazine (24.3 g, 189 mmol) in CHCl3 (100 mL). Add benzamide (100 mg, 0.8 mmol) and heat to reflux. At reflux, add solid trichloroisocyanuric acid (17.6 g, 75.6 mmol) and continue to reflux for 96 h. Cool and filter through 200 g silica gel, eluting with methylene chloride. Purify by silica gel chromatography using a gradient of 35% chloroform/hexane to 60% chloroform/hexane over one hour. Obtain the title compound as a colorless oil, 5.39 g pure title compound and 9.4 g that is >70% desired product. 1H-NMR (CDCl3) δ 8.50 (d, 1H, J=2.2 Hz), 8.37 (d, 1H, J=2.6 Hz), 4.80 (s, 2H), 2.50 (s, 3H); GC/MS M=162+164.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:22])=[C:4]([CH:20]=[O:21])[C:5]2[CH:6]=[CH:7][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]=2[CH:10]=1.[C:23]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O.C(Cl)Cl>[F:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([CH:20]=[O:21])[C:5]2[CH:6]=[CH:7][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]=2[CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1c(O)c(F)cc2c1ccn2S(=O)(=O)c1ccccc1
Agent: [K+]
Solvent: ClCCl
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(F)cc2c(ccn2S(=O)(=O)c2ccccc2)c1C=O
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
Crude 6-fluoro-5-hydroxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (85 mg, 266 μmol; Intermediate 96) was suspended in acetone (5 mL) and treated with K2CO3 (73.6 mg, 532 μmol) and MeI (49.7 μL, 798 μmol) and stirred in a sealed tube at 65° C. for 1 h 30 min. The reaction mixture was cooled to rt and diluted with CH2Cl2, washed with H2O, dried (Na2SO4) and the solvent removed in vacuo to give 6-fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde as an intense yellow, vitreous solid (72.3 mg), 65% pure according to LC/MS, which was directly used in the subsequent Grignard addition.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:31]=[CH:30][C:9]([O:10][C:11]2[CH:12]=[C:13]([CH:27]=[CH:28][CH:29]=2)[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[O:15])=[C:8]([N+:32]([O-:34])=[O:33])[CH:7]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:7]2[C:8]([N+:32]([O-:34])=[O:33])=[C:9]([O:10][C:11]3[CH:12]=[C:13]([CH:27]=[CH:28][CH:29]=3)[C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:26])[F:25])[CH:18]=3)=[O:15])[CH:30]=[CH:31][C:6]=2[N:5]=1
Reactant: Nc1ccc(Oc2cccc(C(=O)Nc3cccc(C(F)(F)F)c3)c2)c([N+](=O)[O-])c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(Oc3cccc(C(=O)Nc4cccc(C(F)(F)F)c4)c3)c([N+](=O)[O-])c2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
To a solution of potassium thiocyanate (740 mg, 7.64 mmol) in acetic acid (22 mL) was added 3-(4-amino-2-nitrophenoxy)-N-[3-(trifluoromethyl)phenyl]benzamide (800 mg, 1.91 mmol), and the mixture was stirred at room temperature for 10 min. A solution of bromine (320 mg, 2.00 mmol) in acetic acid (12 mL) was slowly added dropwise to the obtained solution, and the mixture was stirred at room temperature for 6 hr. The resulting yellow insoluble material was filtered off and washed with acetic acid. The filtrate and washings were combined and the mixture was concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (100 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (100 mL×2) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=30/70→100/0), and the obtained solution was concentrated under reduced pressure to give the title compound (290 mg, 32%) as a red-orange powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([Cl:12])[N:3]=1.[OH:13][CH:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)[CH3:15]>>[Cl:12][C:4]1[N:3]=[C:2]([O:13][CH:14]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH3:15])[C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: COC(=O)c1ccc(C(C)O)cc1
Reactant: Clc1cc2ccccc2c(Cl)n1
Product: COC(=O)c1ccc(C(C)Oc2nc(Cl)cc3ccccc23)cc1

Procedure:
The title compound was prepared from 1,3-dichloroisoquinoline and racemic methyl 4-(1-hydroxyethyl)benzoate as described in the preparation of INTERMEDIATE 3. 1H NMR (500 MHz, CDCl3): δ 8.35 (d, J=8.4 Hz, 1H); 8.08 (d, J=8.3 Hz, 2H); 7.72-7.68 (m, 2H); 7.64 (d, J=8.3 Hz, 2H); 7.60-7.56 (m, 1H); 7.31 (s, 1H); 6.56 (q, J=6.6 Hz, 1H); 3.95 (s, 3H); 1.81 (d, J=6.5 Hz, 3H). LCMS1 4.26 min. (M-(CH3CHPhCO2Me)+H)=180
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[CH2:12][C@@H:11]([N:23]2[C:27]3[N:28]=[CH:29][N:30]=[C:31]([NH:32][C@@H:33]4[C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[CH2:35][CH2:34]4)[C:26]=3[CH:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.C(O)(=O)C>O1CCCC1>[Si:1]([O:8][C@H:9]1[CH2:10][C@H:11]([N:23]2[C:27]3[N:28]=[CH:29][N:30]=[C:31]([NH:32][C@@H:33]4[C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[CH2:35][CH2:34]4)[C:26]=3[CH:25]=[CH:24]2)[CH2:12][C@H:13]1[CH2:14][OH:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@H]1CO
Temperature: 40 °C

Procedure:
7-[(1R,3S,4S)-3-[tert-butyl(dimethyl)silyl]oxy-4-([tert-butyl(dimethyl)silyl]-oxymethyl)cyclopentyl]-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.66 g, 0.00280 mol) was dissolved in a mixture of tetrahydrofuran (6.6 mL), water (6.6 mL, 0.36 mol), and acetic acid (19 mL, 0.34 mol). The solution was then heated to 40° C. overnight. The mixture was then cooled and evaporated, azeotroped with toluene (2×50 mL) and the residue was purified by silica gel chromatography eluting with 0 to 100% ethyl acetate in dichloromethane to yield the product as a white solid, 1.05 g (74%). LC/MS: Rt=1.68 min, ES+ 479 (AA standard).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][NH:7][CH3:8])[CH3:3].C(N(CC)CC)C.[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:8][N:7]([S:17]([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:9]
Reactant: CCOC(=O)CNC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN(C)S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 105 %

Procedure:
An ice cold suspension of sarcosine ethyl ester hydrochloride salt (3.1 g, 20 mmol) in CH2Cl2 (150 mL) was sequentially treated with triethyl amine (4.45 g, 44 mmol) and tosyl chloride (4.19 g, 22 mmol) and stirred for 1 h, after which time the ice bath was removed, and the reaction was allowed to stir for an additional 1 h. The reaction mixture was then partitioned between water and CH2Cl2 and the organic extract was washed with brine, dried, filtered, and concentrated to give 5.7 g of the title compound as a white solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]1[CH2:19][CH2:20][N:21]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:22][CH2:23]1
Reactant: COCCCCCOC1CCNCC1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCCCCOC1CCN(c2ccc(C#N)cc2)CC1
Yield: 31.6 %

Procedure:
A solution of 4-fluorobenzonitrile (0.38 g), 4-(5-methoxypentyloxy)piperidine (0.62 g) and potassium carbonate (0.87 g) in DMF (8 ml) was stirred at 90-95° C. for 6 hours. The reaction mixture was poured into water (50 ml) and extracted twice with a mixture of ethyl acetate and n-hexane (50 ml:20 ml). The extracts were combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 ml) eluting with a mixture of n-hexane and ethyl acetate (5:1 v/v-2:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give 4-(5-methoxypentyloxy)-N-(4-cyanophenyl)piperidine (294 mg).
Reaction SMILES: [N:1]1([C:7]2[N:16]=[C:15]([NH2:17])[C:14]3[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:22]1([N:27]=[C:28]=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCOCC1>[CH:22]1([NH:27][C:28]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[N:16]=[C:15]([NH2:17])[C:14]4[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=4)[N:8]=3)[CH2:2][CH2:3]2)=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C=NC1CCCC1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Solvent: C1COCCO1
Product: COc1cc2nc(N3CCN(C(=O)NC4CCCC4)CC3)nc(N)c2cc1OC
Yield: 83.6 %

Procedure:
In 30 ml of dioxane, there was dissolved 1.16 g. (4 mmole) of 2-piperazino-4-amino-6,7-dimethoxyquinazoline. To the resultant solution was added dropwise 0.45 g. (4 mmole) of cyclopentyl isocyanate at room temperature and the mixture was stirred overnight at room temperature. The precipitated crystals were recovered by filtration to obtain 1.34 g. of the desired product.
Reaction SMILES: [Br:1][C:2]1[C:15](=[O:16])[N:14]([CH3:17])[C:5]2[N:6]=[C:7](S(C)(=O)=O)[N:8]=[CH:9][C:4]=2[CH:3]=1.[CH3:18][NH2:19].C(O)C>CC(O)C>[Br:1][C:2]1[C:15](=[O:16])[N:14]([CH3:17])[C:5]2[N:6]=[C:7]([NH:19][CH3:18])[N:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: CN
Reactant: Cn1c(=O)c(Br)cc2cnc(S(C)(=O)=O)nc21
Solvent: CC(C)O
Solvent: CCO
Product: CNc1ncc2cc(Br)c(=O)n(C)c2n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
Charged a flask with 6-bromo-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.910 g, 2.86 mmol, prepared by reference in Scheme 6E) and 10.0 mL IPA. Chilled suspension to 0° C. and treated with methylamine 33% wt. solution in ethanol (1.78 ml, 14.3 mmol). After addition was complete, the bath was removed and the reaction mixture was allowed to warm to ambient temperature and stirred overnight. The crude reaction mixture was filtered and washed with ethanol (2×30 mL) and air-diced to afford a white microcrystalline solid: 6-bromo-8-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (0.637 g, 82.8% yield). MS (M+H)+ 269, 271.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[CH3:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[C:32]([CH3:36])[C:33]=1[O:34][CH3:35]>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:30]2[CH:31]=[C:32]([CH3:36])[C:33]([O:34][CH3:35])=[C:28]([CH3:27])[CH:29]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: COc1c(C)cc(B(O)O)cc1C
Product: COc1c(C)cc(-c2cncc(O[C@@H]3SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c2)cc1C

Procedure:
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 3,5-dimethyl-4-methoxyphenylboronic acid, 5-(3,5-dimethyl-4-methoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=52%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1.[N-:22]=[N+:23]=[N-:24].[Li+]>CS(C)=O>[N:22]([CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)=[N+:23]=[N-:24]
Reactant: COC(=O)C(Oc1ccc(CBr)cc1)c1ccccc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: CS(C)=O
Product: COC(=O)C(Oc1ccc(CN=[N+]=[N-])cc1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A concentrated stirred solution of the product of Step D in anhydrous dimethylsulfoxide (DMSO) is treated at ambient temperature with lithium azide (25% excess) portionwise. The mixture is then stirred at ambient temperature under protection from moisture for about 1 hour, or until TLC indicates complete reaction. The mixture is then partitioned between ether (or ethyl acetate) and water. The organic phase is washed repeatedly with H2O, then dried over MgSO4, filtered, and concentrated. The residue may be purified by chromatography on silica gel.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[S:15][C:16]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18][C:17]=2[N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:13][C:14]1[S:15][C:16]2[CH2:22][CH2:21][N:20]([C:2]3[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=3[N+:10]([O-:12])=[O:11])[CH2:19][CH2:18][C:17]=2[N:23]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: Cc1nc(Br)c([N+](=O)[O-])c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(N2CCc3nc(N)sc3CC2)c([N+](=O)[O-])c(=O)[nH]1

Procedure:
In analogy to the procedure described in example 1c 6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one as prepared in example 1a was treated with 2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine [Ger. Offen. (1989), DE 3820775] in N,N-dimethylformamide in the presence of potassium carbonate at 110° C. to yield the title compound as yellow solid; m.p. >200° C.; MS: [M+H]+=323.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:8]1)(=O)C.[OH-].[K+].C(O)C>O>[OH:4][CH2:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:8]1
Reactant: CC(=O)OCCC1CN(C(=O)OCc2ccccc2)CCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCOC(CCO)C1
Yield: 70.9 %

Procedure:
A mixture of 2-(2-acetoxyethyl)-4-benzyloxycarbonylmorpholine (24.5 g), potassium hydroxide (8.9 g), ethanol (40 ml), and water (40 ml) is refluxed for 30 minutes and concentrated under reduced pressure. Water is added to the residue and the mixture is extracted with diethyl ether. The organic layer is washed with water, dried over sodium sulfate, and evaporated to give the title compound (15 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:7][CH2:6][CH:5]([N:8]([C@H:18]2[CH2:22][CH2:21][NH:20][CH2:19]2)[C:9](=[O:17])[C:10]([CH3:16])([CH3:15])[C:11]([OH:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[C:24]([N:28]1[CH2:32][C@@H:31]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[C@H:30]([C:40](O)=[O:41])[CH2:29]1)([CH3:27])([CH3:26])[CH3:25]>>[ClH:39].[C:24]([N:28]1[CH2:32][C@@H:31]([C:33]2[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=2)[C@H:30]([C:40]([N:20]2[CH2:21][CH2:22][C@H:18]([N:8]([CH:5]3[CH2:6][CH2:7][C:2]([CH3:23])([CH3:1])[CH2:3][CH2:4]3)[C:9](=[O:17])[C:10]([CH3:15])([CH3:16])[C:11]([OH:14])([CH3:12])[CH3:13])[CH2:19]2)=[O:41])[CH2:29]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)N1C[C@@H](C(=O)O)[C@H](c2ccc(Cl)cc2)C1
Reactant: CC1(C)CCC(N(C(=O)C(C)(C)C(C)(C)O)[C@H]2CCNC2)CC1
Product: CC1(C)CCC(N(C(=O)C(C)(C)C(C)(C)O)[C@H]2CCN(C(=O)[C@@H]3CN(C(C)(C)C)C[C@H]3c3ccc(Cl)cc3)C2)CC1
Product: Cl

Procedure:
The title compound was prepared according to the procedure described in Step F, G of Example A1, using N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2,3-trimethyl-N-[(3S)-pyrrolidine-3-yl]butaneamide (62 mg, 0.19 mmol) prepared in Step B and (3S,4R)-1-t-butyl-4-(4-chlorophenyl)pyrrolidine-3-carboxylic acid prepared in Preparation Example A9-2 (99 mg, 89%).
Reaction SMILES: [Zr:1].[P:2](=[O:6])([OH:5])([OH:4])[OH:3]>>[P:2](=[O:3])([OH:6])([OH:5])[OH:4].[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[Zr+4:1].[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[Zr+4:1].[Zr+4:1]
Reactant: [Zr]
Agent: O=P(O)(O)O
Product: O=P([O-])([O-])[O-]
Product: [Zr+4]

Procedure:
Recent advances in sol gel precipitation provide a method of synthesizing zirconium phosphate particles that avoids the creation of soft gel particles and/or that avoids agglomeration of zirconium phosphate gel particles. U.S. Patent Application Publication No. 2006/0140840, which is incorporated in its entirety by reference herein, describes a method for synthesizing zirconium phosphate particles that utilizes organic chemical additives to suppress gelation and agglomeration in order to control particle size of the product. The additive is added to a zirconium oxychloride solution and can form a complex with zirconium ions in the solution and thereby reduce hydration of the zirconium ions. The solution can then be combined with phosphoric acid or a phosphoric acid salt to obtain zirconium phosphate particles by sol gel precipitation. The method can synthesize zirconium phosphate particles having a controlled particle size or particle size distribution. Zirconium phosphate particles synthesized by this method can have, for example, a particle size distribution of less than 20% in the range of >60-120 microns, more than 80% in the range of 30-60 microns, and less than 10% in the range of less than 30 microns. The particles can also have an ammonia capacity in dialysate solution of about 15-20 mg NH4+—N/g ZrP, when exposed to an NH4+—N/g concentration of 100 mg/dL.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:8]=[C:9]([CH2:22][C:23](Cl)=[N:24][OH:25])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1.[C:27]([C:29]1[C:30]([NH2:36])=[N:31][C:32]([NH2:35])=[CH:33][CH:34]=1)#[CH:28].C(N(CC)CC)C>O>[F:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1)[CH2:22][C:23]1[CH:28]=[C:27]([C:29]2[C:30]([NH2:36])=[N:31][C:32]([NH2:35])=[CH:33][CH:34]=2)[O:25][N:24]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(OCc2ccc(F)cn2)c(F)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4ccc(F)cn4)c(F)c3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a tetrahydrofuran (5.00 mL) solution of (3-fluoro-4-(5-fluoro-pyridin-2-ylmethoxy)-phenyl)-acetohydroximoyl chloride (170 mg, 0.554 mmol) described in Manufacturing Example 94-1-3 and 3-ethynyl-pyridin-2,6-diamine (40.0 mg, 0.300 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (125 μL, 0.900 mmol) at room temperature, which was stirred for 30 minutes at room temperature. Water was added to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1→3:1) to obtain the title compound (59.0 mg, 48.0%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O.C(Cl)(Cl)Cl>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(OCCCCCBr)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.15 %

Procedure:
A solution of N-(4-hydroxyphenyl)-acetamide (paracetamol) (1) (1.50 g, 0.01 mol) and 1,5-dibromopentane (9) (10.0 ml) in ethyl methyl ketone (25.0 ml) containing potassium carbonate (5.0 g) was stirred for 8 hr at room temperature. The reaction mixture was filtered, residue washed with ethyl methyl ketone and solvent evaporated under reduced pressure to get the residue. The residue was dissolved in chloroform (200.0 ml), washed with 5% sodium hydroxide solution (3×100 ml), water (3×50 ml), dried, filtered and crystallized from methanol to get the desired product N-[4-(5-bromo-pentoxy)-phenyl]-acetamide (11) (2.15 g, 72.15%), mp 110-111° C.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][N:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]1=[O:17].FC(F)(F)C(O)=O>O>[O:17]=[C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[N:13][CH:12]=2)[N:7]1[CH2:6][CH:2]=[O:1]
Reactant: O=c1ccc2cnccc2n1CC1OCCO1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=CCn1c(=O)ccc2cnccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 0.60 g of 1-(1,3-dioxolan-2-ylmethyl)-1,6-naphthyridin-2(1H)-one, 6 mL of a 90% aqueous trifluoroacetic acid solution was added, and the mixture was stirred at room temperature for 12 hours. Thereto was added 1.0 mL of water, and the mixture was stirred for 1 hour, and stirred at 55 to 75° C. for 3 hours 30 minutes. The solvent was distilled off under reduced pressure, thereto were added a saturated aqueous sodium hydrogen carbonate solution and chloroform, and the mixture was stirred at room temperature for 1 hour 30 minutes. The organic layer was then separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain (2-oxo-1,6-naphthyridin-1(2H)-yl)acetaldehyde.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[O:15][CH2:14][CH2:13][NH:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:23][CH2:24][CH2:25][CH2:26]I>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH:10]1[O:15][CH2:14][CH2:13][N:12]([CH2:26][CH2:25][CH2:24][Cl:23])[CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCC1CNCCO1
Reactant: ClCCCI
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCC1CN(CCCCl)CCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.1 %

Procedure:
A solution of 2-({[tert-butyl(dimethyl)silyl]oxy}methyl)morpholine (2.1 g, 9.07 mmol) in DCM (20 mL) was treated with triethylamine (3.8 mL, 27.2 mmol) and 1-chloro-3-iodopropane (1.95 mL, 18.1 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure then purified by MPLC (ISCO, 0% MeOH/100% DCM to 25% MeOH/75% DCM). The product was isolated as an oil (560 mg, 20%): HPLC MS RT=2.66 min, MH+=308.4, 310.4; 1H NMR (DMSO-d6) δ: 3.79-3.69 (1H, m), 3.63 (2H, t) 3.59-3.52 (1H, m), 3.50-3.36 (3H, m), 2.73 (1H, d), 2.61 (1H, d), 2.35 (2H, t), 1.94 (1H, td), 1.83 (2H, qt), 1.73 (1H, t), 0.83 (9H, s), 0.00 (6H, s).