Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH:51]1[CH2:56][CH2:55][CH:54]([O:57][C:58]2[CH:65]=[CH:64][CH:63]=[CH:62][C:59]=2[CH:60]=[O:61])[CH2:53][CH2:52]1>CN(C=O)C.O>[CH:60]([C:59]1[CH:62]=[CH:63][CH:64]=[CH:65][C:58]=1[O:57][CH:54]1[CH2:55][CH2:56][N:51]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]2[CH:17]=[C:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:20][N:19]=2)=[O:22])[CH2:52][CH2:53]1)=[O:61]
Reactant: O=Cc1ccccc1OC1CCNCC1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=Cc1ccccc1OC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Reaction time: 0.03 h
Yield: 43.4 %

Procedure:
DIPEA (360 mg, 2.8 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (190 mg, 0.8 mmol) in DMF (2.0 mL) followed by HOBt (160 mg, 1.2 mmol) and EDCI.HCl (230 mg, 1.2 mmol). After 2 minutes of stirring, 2-(piperidin-4-yloxy)-benzaldehyde hydrochloride (200 mg, 0.8 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine and concentrated The residue was purified by column chromatography (using neutral alumina and 5% MeOH in CHCl3) to afford 150 mg (44% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-formyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 433.18, 98.8%, 1H NMR (300 MHz, DMSO-d6): δ13.8 (m, 1H), 10.3 (s, 1H), 8.2 (m, 1H), 7.8 (m, 2H), 7.7 (m, 2H), 7.5 (m, 2H), 7.4 (m, 2H), 7.1 (m, 2H), 5.0 (m, 1H), 4.2 (m, 2H), 3.7 (m, 2H), 3.5 (m, 2H), 2.0 (m, 2H), 1.8 (m, 2H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH2:35])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:38]1([S:44](Cl)(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:38]1([S:44]([NH:35][S:34]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:25]2[CH:26]=[CH:27][C:22]([CH2:21][N:6]3[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][N:8]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:16]([F:19])([F:18])[F:17])[C:7]3=[O:20])=[CH:23][CH:24]=2)(=[O:37])=[O:36])(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NS(=O)(=O)c2ccccc2)cc1
Temperature: 60 °C

Procedure:
The title compound was prepared from 5-n-butyl-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 13, Step C) according to the procedure of Example 14, except that a total of 2.4 equivalents of benzenesulfonyl chloride was used, and the mixture was heated at 60° C. for 4 hours. The crude produce was purified by flash chromotography on silica gel (gradient elution with 0.5-5% MeOH in CH2Cl2). The residue from evaporation of the product fractions was partitioned between CH2Cl2 and 1N HCl. The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound as a cream-colored, sticky solid, homogeneous by TLC in 9:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 671 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C(=O)([O-])O.[Na+].[CH:22]1[C:34]2[CH:33]([CH2:35][O:36][C:37](ON3C(=O)CCC3=O)=[O:38])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][C:13]([OH:15])=[O:14])[C:37]([O:36][CH2:35][CH:33]1[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:26]2[C:34]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:38])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCNCC(=O)O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCN(CC(=O)O)C(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 20 h

Procedure:
10.9 g (50 mmol) of N-(2-tert-butoxycarbonylaminoethyl)aminoacetic acid are stirred together with 50 ml of water, 11.3 g (135 mmol) of sodium hydrogen carbonate and 50 ml of tetrahydrofuran. Subsequently, 24.3 g (72 mmol) of N-(9-fluorenylmethoxycarbonyloxy)succinimide are added. The mixture is stirred at room tmeperature for 20 h and the salt removed by filtration; the filtrate is acidified and the phases separated, and the organic phase is then concentrated.
Reaction SMILES: [I:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]([CH2:12][C:13]([OH:15])=O)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH2:18]([O:20][C:21]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[NH:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)=[O:22])[CH3:19].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>CN(C)C=O.C(OCC)(=O)C>[CH2:18]([O:20][C:21]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[N:29]([CH2:30][C:31]1[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=1)[C:13](=[O:15])[CH2:12][C:7]1[NH:6][C:5]2[CH:16]=[CH:17][C:2]([I:1])=[CH:3][C:4]=2[S:9](=[O:10])(=[O:11])[N:8]=1)=[O:22])[CH3:19]
Reactant: CCOC(=O)C1CCCCC1NCc1ccc(F)cc1
Reactant: O=C(O)CC1=NS(=O)(=O)c2cc(I)ccc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCCCC1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2cc(I)ccc2N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(7-Iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 24b, 2.62 g, 7.16 mmol) was dissolved in anhydrous N,N-dimethylformamide (30 mL). 2-(4-Fluoro-benzylamino)-cyclohexanecarboxylic acid ethyl ester (2.0 g, 7.16 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.44 g, 7.52 mmol). Then N-methylmorpholine (1.52 g, 15.04 mmol) was added into the above reaction mixture. The mixture stirred at 25° C. for 24 h. The solution was diluted with ethyl acetate (200 mL), washed with 1.0 M aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution and saturated aqueous brine solution. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford the crude product, 2-{(4-fluoro-benzyl)-[2-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclohexanecarboxylic acid ethyl ester, as a yellow oil, which was used directly in the next step without further purification. LC-MS (ESI) calcd for C25H27FIN3O5S 627.07, found 628.3 [M+H+].
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][NH:3][CH:2]2[C:7]([NH:9][C:10]1[C:11]([F:24])=[CH:12][C:13]([Cl:23])=[C:14]([CH:16]=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:15]=1)=[O:8].C(N(CC)CC)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl.O>C(Cl)Cl>[Cl:23][C:13]1[CH:12]=[C:11]([F:24])[C:10]([N:9]2[C:7](=[O:8])[CH:2]3[CH:1]4[CH2:6][CH:5]4[CH2:4][N:3]3[C:33]2=[O:35])=[CH:15][C:14]=1[CH:16]=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)C=Cc1cc(NC(=O)C2NCC3CC32)c(F)cc1Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1cc(N2C(=O)C3C4CC4CN3C2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of the compound of Step G, Example 2, (300.0 mg, 0.85 mmol) and triethylamine (1.18 mL, 8.5 mmol) in CH2Cl2 (50 mL), under N2, at room temperature, was added dropwise a solution of triphosgene (84.0 mg, 0.28 mmol) in CH2Cl2 (10 mL) over a period of 15 minutes. The solution was stirred at room temperature for 10 minutes. A mixture of CH2Cl2 (100 mL) and H2O (50 mL) was added. The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure to dryness. The residue was chromatographed on silica gel using 25% ethyl acetate in hexane as eluent. Fractions containing the title compound were combined and evaporated under reduce pressure to yield the title compound, a compound of the invention, as a white solid (84.0 mg), 26%; m.p. 154°-156° C., IR (nujol, cm-1): 1720.4 (C=O); 1H NMR δ: 0.61-0.63 (q,1H), 1.32-1.36 (m,4H), 2.01-2.03 (m,1H), 2.11-2.18 (m,1H), 3.12-3.18 (d,1H), 4.18-4.28 (m,4H), 6.37-6.41 (d,1H), 7.32-7.35 (d,1H), 7.59-7.62 (d,1H), 7.94-7.99 (d,1H).
Reaction SMILES: [CH2:1]([S:3][C:4]([CH3:8])([CH3:7])[C:5]#[N:6])[CH3:2].[Cl:9]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:9][CH:1]([S:3][C:4]([CH3:8])([CH3:7])[C:5]#[N:6])[CH3:2]
Reactant: CCSC(C)(C)C#N
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Cl)SC(C)(C)C#N
Reaction time: 4 h
Yield: 101.5 %

Procedure:
In 10 ml of carbon tetrachloride were placed 1.4 g of 2-(ethylthio)-2-methylpropanenitrile and 1.5 g of N-chlorosuccinimide and the mixture was refluxed with stirring for four hours. Solid was filtered and the filtrate was evaporated to give 1.8 g of product as a yellow liquid. This product was used without purification.
Reaction SMILES: [C:1](OC)(=O)[CH2:2][C:3]([O-:5])=[O:4].[CH3:9][NH:10][CH3:11].[CH2:12]=O>O>[CH3:9][N:10]([CH3:12])[CH2:11][CH:2]([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CNC
Reactant: C=O
Reactant: COC(=O)CC(=O)[O-]
Solvent: O
Product: CC(CN(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In 1.0 ml of water was dissolved 1.5 g of methyl malonate, after which 1.26 g of a 50% aqueous dimethylamine solution and 0.96 ml of a 37% aqueous formaldehyde solution were added with stirring at 0° C., and the resulting mixture was stirred at 0° to 5° C. for 3 hours and then at 80° C. for 30 minutes.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=3)[CH:17]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C-]#N.[K+].[N:34]12CCN(CC1)C[CH2:35]2.CC(O)=O>O.CS(C)=O>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([C:35]#[N:34])[N:24]=3)[CH:17]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CN2CCN1CC2
Reactant: CC(C)(C)OC(=O)NCCc1ccc(-c2cccc(Oc3ccnc(Cl)n3)c2)cc1
Agent: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)NCCc1ccc(-c2cccc(Oc3ccnc(C#N)n3)c2)cc1
Reaction time: 4 h

Procedure:
A mixture of {2-[3′-(2-chloro-pyrimidin-4-yloxy)-biphenyl-4-yl]-ethyl}carbamic acid tert-butyl ester (150 mg), potassium cyanide (76 mg) and 1,4-diazabicyclo[2,2,2]octane (13 mg) in water (0.4 ml) and DMSO (2 ml) is left at 5° C. for 4 h. This mixture is acidified with AcOH to pH 4-5, quenched with brine and extracted twice with diethyl ether. The combined organic phases are dried over sodium sulfate, the solvent is evaporated and the crude product is purified on silica (15 g) with cyclohexane/EtOAc=5/1 to afford pure {2-[3′-(2-cyano-pyrimidin-4-yloxy)-biphenyl-4-yl]-ethyl}carbamic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2](=O)[C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].CC1C=CC(S(Cl)(=O)=O)=CC=1.N1C=CC=CC=1.C(OC(=O)C)(=O)C>C(Cl)Cl>[C:2]([C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4])#[N:1]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(N)=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C[C@H](C#N)NC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 37.2 %

Procedure:
To a solution of (R)-tert-butyl 1-amino-1-oxopropan-2-ylcarbamate (Int-X-A, 1 g, 5.31 mmol) and 4-methylbenzene-1-sulfonyl chloride (4.05 g, 21.25 mmol) in CH2Cl2 (5 mL) was added pyridine (2.101 g, 26.6 mmol). After 3 h, acetic anhydride (0.651 g, 6.38 mmol) was added. This was stirred overnight before it was concentrated and EtOAc was added. Saturated NaHCO3 was added and the two phase mixture was stirred vigorously for 2 h. The organic layer was washed with 1 N HCl and then saturated NaHCO3. The organic layer was dried and concentrated. The resulting residue was purified by flash chromatography (Isco Combiflash Companion, 40 g silica gel, 15% ethyl acetate-hexane) to provide the product (R)-tert-butyl 1-cyanoethylcarbamate (Int-X-B, 336 mg, 1.974 mmol, 37.2% yield); [M+Na]+=193.2; 1H NMR (400 MHz, methanol-d4) δ ppm 4.51 (1 H, q), 1.34-1.58 (12 H, m).
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15](=[O:23])[NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=2)[CH2:7]1)(=O)=O.[C:24]([O-:27])(=[S:26])[CH3:25].[K+]>CN(C)C=O>[C:24]([S:26][CH:6]1[CH2:7][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15](=[O:23])[NH:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:14]=2)[CH2:9]1)(=[O:27])[CH3:25]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)OC1CN(c2nc(C(=O)Nc3ccccc3)cs2)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)Nc3ccccc3)cs2)C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 69.6 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-(4-phenylcarbamoyl-1,3-thiazol-2-yl)azetidine (1.28 g, 3.85 mmol) (obtained as described in Reference Example 32(3)) in dimethylformamide (40 ml) was added potassium thioacetate (2.60 g, 23.1 mmol) at room temperature. The mixture was stirred in an oil bath (90° C.) for 3 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:2) as the eluant to afford 3-acetylthio-1-(4-phenylcarbamoyl-1,3-thiazol-2-yl)azetidine (893 mg, yield 70%) as a pale brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH2:5][C:4](=[O:15])[CH:3]=1.CO[CH:18](OC)[CH2:19][C:20](=O)[CH3:21].[OH-].[K+]>C(O)C.C1(C)C=CC=CC=1>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH:6]1[CH2:7][C:2]2[N:1]=[CH:18][CH:19]=[C:20]([CH3:21])[C:3]=2[C:4](=[O:15])[CH2:5]1
Reactant: COC(CC(C)=O)OC
Reactant: NC1=CC(=O)CC(c2ccccc2Cl)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccnc2c1C(=O)CC(c1ccccc1Cl)C2
Yield: 75.5 %

Procedure:
To a solution of 1-amino-5-(2-chlorophenyl)cyclohexen-3-one (2.7 g) in ethanol (50 ml) and toluene (150 ml) were added acetylacetoaldehyde-dimethylacetal (4.0 g) and 85% potassium hydroxide (0.67 g), and the mixture was refluxed. With intervals of 30 minutes, 85% potassium hydroxide (0.14 g) was added 3 times to the mixture. Then, the mixture was refluxed for 1 hour. Under reduced pressure, the solvent was evaporated, and to the residue was added ethyl acetate. The mixture was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was subjected to silica gel column chromatography (EtOAc/hexane) to give crystals of 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (2.5 g).
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:10]=[CH:11][C:12]3[C:18](=[O:19])[C:17]([C:20]([OH:22])=[O:21])=[CH:16][NH:15][C:13]=3[N:14]=2)[CH2:5][CH2:4]1)=[O:2].C(N(CC)CC)C.ClC(OC(C)C)=O.O[N:38]1[C:42](=[O:43])[CH2:41][CH2:40][C:39]1=[O:44]>ClCCl.CN(C)C=O>[CH:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:10]=[CH:11][C:12]3[C:18](=[O:19])[C:17]([C:20]([O:22][N:38]4[C:42](=[O:43])[CH2:41][CH2:40][C:39]4=[O:44])=[O:21])=[CH:16][NH:15][C:13]=3[N:14]=2)[CH2:5][CH2:4]1)=[O:2]
Reactant: O=C1CCC(=O)N1O
Reactant: O=CN1CCN(c2ncc3c(=O)c(C(=O)O)c[nH]c3n2)CC1
Agent: CC(C)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=CN1CCN(c2ncc3c(=O)c(C(=O)ON4C(=O)CCC4=O)c[nH]c3n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
A suspension of 5,8-dihydro-2-(4-formyl-1-piperazinyl)-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid (273 g) and triethylamine (299 ml) in dried dichloromethane (3500 ml) was stirred well at room temperature for one hour. To the suspension, isopropyl chloroformate (221 g) was added dropwise with cooling at 0°-10° C. and the reaction mixture was stirred for 2 hours. A solution of N-hydroxysuccinimide (207 g) in dimethylformamide (350 ml) was added to the mixture and the resulting mixture was kept at 5°-10° C. for additional 2 hours. The crystalline product was collected by filtration and washed successively with water (2000 ml) and acetone (2000 ml) to give N-[5,8-dihydro-2-(4-formyl-1-piperazinyl)-5-oxopyrido[2,3-d]pyrimidine-6-carbonyloxy] succinimide (326 g). m.p. above 300° C.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH2:16]([I:19])[CH2:17][CH3:18].C(OCC)C>C(#N)C>[I-:19].[CH3:1][N:2]([CH3:15])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][N+:12]([CH2:16][CH2:17][CH3:18])=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: CCCI
Reactant: CN(C)c1ccc(-c2ccncc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: CCC[n+]1ccc(-c2ccc(N(C)C)cc2)cc1
Product: [I-]
Temperature: 25 °C

Procedure:
N,N-dimethyl-4-(pyridine-4-yl) aniline (0.2 g, 11 mmols) was dissolved in acetonitrile (50 ml) and propyl iodide (4 ml) was added. The mixture was heated at reflux for 4 hours then cooled to ambient temperature. Diethylether (50 ml) was added IDT322 (0.11 g, 2.9 mmols) crystallized upon standing and was removed via filtration. 1H NMR (DMSO-d6) δ 1.40 (t, 3H), 1.92 (q, 2H) 3.40 (s, 6H), 4.45 (t, 2H), 6.85 (t, 2H), 8.02 (d, 2H), 8.39 (d, 2H), 8.82 (d, 2H).
Reaction SMILES: [Cl-].[Li+].[CH2:3]([N:9]1[CH:14]=[C:13](I)[C:12]([CH3:16])=[C:11]([N+:17]([O-:19])=[O:18])[C:10]1=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:21]1([Sn](CCCC)(CCCC)CCCC)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.C(OCC)(=O)C>[CH2:3]([N:9]1[CH:14]=[C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:12]([CH3:16])=[C:11]([N+:17]([O-:19])=[O:18])[C:10]1=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: CCCCCCn1cc(I)c(C)c([N+](=O)[O-])c1=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCn1cc(-c2ccccc2)c(C)c([N+](=O)[O-])c1=O
Yield: 72.2 %

Procedure:
A mixture of bis(triphenylphosphine)Pd(II) chloride (0.014 g), lithium chloride (0.067 g), 1-hexyl-5-iodo-4-methyl-3-nitro-2-pyridone (0.15 g, 0.41 mmol) and phenyltributyltin (0.11 mL, 0.62 mmol) in THF (15 mL) was heated under reflux for 2 days. The mixture was cooled, diluted with ethyl acetate, and washed with aqueous potassium fluoride and water. The organic phase was dried, filtered and evaporated. Chromatography of the residue over silica gel (petroleum ether/methylene chloride 1/1 to methylene chloride is gradient) gave 1-hexyl-4-methyl-3-nitro-5-phenyl-2-pyridone (0.093 g, 72%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5](Br)=[C:4]([Cl:12])[CH:3]=1.[CH3:13][C@@H:14]1[CH2:19][NH:18][CH2:17][CH2:16][NH:15]1>>[ClH:1].[Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([N:18]2[CH2:17][CH2:16][NH:15][C@H:14]([CH3:13])[CH2:19]2)=[C:4]([Cl:12])[CH:3]=1
Reactant: Clc1cc(Cl)c2ccoc2c1Br
Reactant: C[C@@H]1CNCCN1
Product: C[C@@H]1CN(c2c(Cl)cc(Cl)c3ccoc23)CCN1
Product: Cl

Procedure:
Beginning with 0.31 gm (1.2 mmol) 4,6-dichloro-7-bromobenzofuran and 0.12 gm (1.2 mMol) 2(R)-methylpiperazine, the title compound was prepared essentially as described in GENERAL PROCEDURE IV.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][NH2:4].[CH2:5]1[O:7][CH:6]1[CH2:8][Cl:9].Cl.[OH-:11].[Na+].[C:13](=[O:15])=[O:14]>O>[CH2:1]=[CH:2][CH2:3][NH3+:4].[CH2:5]1[O:7][CH:6]1[CH2:8][Cl:9].[C:13]([O-:15])([OH:14])=[O:11].[C:13](=[O:7])([OH:15])[O-:14]
Reactant: C=CCN
Reactant: [OH-]
Reactant: O=C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCC1CO1
Product: C=CC[NH3+]
Product: O=C([O-])O
Temperature: 36 °C

Procedure:
1.4 kg of water is loaded into a 2 liter glass reactor. The temperature is set to 35° C. and 100 g of sevelamer hydrochloride is added in portions, stirring the mixture. A solution of 30% sodium hydroxide is then added until pH 12 is reached (around 71 g) and gaseous carbon dioxide is bubbled through. The temperature is maintained at 35-37° C. until pH 7.2 is reached. The mixture is maintained at 35° C. under stirring for 2 hours and if necessary further carbon dioxide is bubbled through until the pH is stabilized at 7.2. The suspension is filtered, the solid washed repeatedly with water to eliminate as much of the residual chlorine as possible. The solid thus obtained is dried and ground.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH3:11])[N:3]=1.C(#[N:20])C.[NH4+].[OH-]>O>[NH2:20][C:6]1[CH:7]=[C:2]([Cl:1])[N:3]=[C:4]([S:9][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH3:11])[N:5]=1
Reactant: CC(Sc1nc(Cl)cc(Cl)n1)c1ccccn1
Reactant: CC#N
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(Sc1nc(N)cc(Cl)n1)c1ccccn1
Temperature: 35 °C
Reaction time: 15 h
Yield: 94 %

Procedure:
A flask is charged with 4,6-dichloro-2-(1-(2-pyridyl)ethyl)thio-pyrimidine (0.560 g, 1.96 mmol), acetonitrile (6.5 ml) and 13 ml of 29 % NH4OH. The contents are stirred at 35° C. for 15 h, poured into 50 ml of water, extracted once with ethyl acetate. The organic layer is washed with a saturated solution of brine (1×30 ml), dried with anhydrous Na2SO4 and concentrated in vacuo. Chromatography is accomplished with 100 g of silica gel, packed and eluted with ethyl acetate-hexane (2:3), to yield 0.491 g (94%) of 4-amino-6-chloro-2-(1-(2-pyridyl)ethyl)thio-pyrimidine.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[N:26]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(CC)CC)C>ClCCl>[CH3:1][N:2]([CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1)[C:31]([N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:32]
Reactant: CNC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Reactant: O=C(Cl)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1C2CCC3C4CC=C5CC(N(C)C(=O)N6CCCC6)CCC5(C)C4CCC32CN1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A mixture of compound 7B (10.7 mg, 0.031 mmol), 1-pyrrolidinecarbonyl chloride (13 μL, 3.0 eq), triethylamine (26 μL, 6.0 eq) and dichloromethane (1 mL) was stirred at room temperature overnight. The clear solution was directly loaded on silica gel column and eluted with 0.5% ammonium hydroxide and 5% methanol in dichloromethane to give the desired product (12 mg, 87% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].C(N(CC)CC)C.[C:17](Cl)(Cl)=[S:18]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:6]=[C:17]=[S:18]
Reactant: S=C(Cl)Cl
Reactant: NCc1cccc(F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Fc1cccc(CN=C=S)c1
Temperature: -10 °C
Reaction time: 2.75 h
Yield: 51.4 %

Procedure:
A solution of 3-fluorobenzylamine (6.3 g, 0.05 mole) and triethylamine (15.4 ml, 0.11 mole) in 50 ml of tetrahydrofuran was added dropwise to a solution of thiophosgene (4.2 ml, 0.055 mole) in 50 ml of tetrahydrofuran with cooling to -10° C. over a period of twenty minutes. The mixture was stirred at 25° C. for 2.75 hours and filtered. The filtrate was treated with charcoal, then filtered and evaporated to an oil. The oil was diluted with hexane:ethyl acetate (90:10) and purified on a flash silica column eluted with hexane:ethyl acetate (90:10) to yield 4.3 g (51%) of 3-fluorobenzyl isothiocyanate as a yellow oil.