Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[NH:15][C:14](=O)[C:7]3[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=3[CH:5]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:14]1[C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[CH:5]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[N:15]=1
Reactant: CSc1ncc2cc(C3CC3)[nH]c(=O)c2n1
Reactant: O=P(Cl)(Cl)Cl
Product: CSc1ncc2cc(C3CC3)nc(Cl)c2n1
Temperature: 70 °C
Yield: 88 %

Procedure:
6-Cyclopropyl-2-(methylthio)pyrido[3,4-d]pyrimidin-8(7H)-one (Preparation 181, 180 mg 0.77 mmole) was stirred with phosphorus oxychloride (6 mL) and the reaction was heated at 70° C. for 2 hours before concentrating in vacuo. Ethyl acetate (20 mL) was added to the residue and the solution was cooled in ice. A little ice and then sodium bicarbonate solution (10 mL) was added. The mixture was shaken thoroughly and the aqueous layer separated. The organic layer was washed with sodium bicarbonate solution (10 mL), brine (5 mL), dried and concentrated in vacuo. The residue was purified using preparative TLC eluting with 1:3 ethyl acetate:cyclohexane to afford the title compound (171 mg 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16]OS(C)(=O)=O.[C-:22]#[N:23].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][C:22]#[N:23]
Reactant: [C-]#N
Reactant: COc1ccc(OC)c(C2CCCC2COS(C)(=O)=O)c1
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(OC)c(C2CCCC2CC#N)c1
Temperature: 100 °C
Yield: 92.4 %

Procedure:
Dissolve methanesulfonic acid 2-(2,5-dimethoxy-phenyl)-cyclopentylmethyl ester (4.8 g, 15 mmol) in DMSO (25 ml), add sodium cyanide (12 g, 16 mmol), and heat at 100° C. over night. Cool to room temperature and quench with water and ethyl acetate. Separate layers, wash organic with water 3×, brine 2×, dry and concentrate to give the title compound (3.4 g 91%): 1H NMR (CDCl3) δ 6.79-6.72 (m,3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.54-3.48 (m, 1H), 2.77-2.70 (m, 1H), 2.17-2.09 (m, 1H), 1.96-1.89 (m, 4H), 1.78-1.59 (m, 3H).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:20]([CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:32]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([Br:40])=[CH:36][C:35]=2[F:41])=[C:31]([CH3:42])[C:30](=[O:43])[N:29]([CH3:44])[CH:28]=1)=O)#[N:21].CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Si]([N:63]=[N+:64]=[N-:65])(C)(C)C>CC#N.C(OCC)(=O)C>[Br:40][C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:32]2[C:27]([C:25]3[N:24]([CH2:23][CH2:22][C:20]#[N:21])[N:65]=[N:64][N:63]=3)=[CH:28][N:29]([CH3:44])[C:30](=[O:43])[C:31]=2[CH3:42])=[C:35]([F:41])[CH:36]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Cc1c(Nc2ccc(Br)cc2F)c(C(=O)NCCC#N)cn(C)c1=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1c(Nc2ccc(Br)cc2F)c(-c2nnnn2CCC#N)cn(C)c1=O
Reaction time: 22 h
Yield: 61 %

Procedure:
PPh3 (83 mg, 0.32 mmol) was added to a stirred suspension of 4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (2-cyano-ethyl)-amide (51 mg, 0.12 mmol) in MeCN (1.5 mL). DIAD (0.065 mL, 0.31 mmol) and TMSN3 (0.045 mL, 0.32) were added dropwise. After 22 hours, the reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography gave clean desired product (33 mg, 61%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].[C:17](OC)(OC)(OC)C>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH3:17])=[O:7])([O-:3])=[O:2]
Reactant: COC(C)(OC)OC
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A mixture of 2-nitro-4-trifluoromethylbenzoic acid (23.5 g, 0.10 mol), trimethyl orthoacetate (60.1 g, 0.50 mol) and toluene (60 ml) was heated at 80° C. for 16 h. The reaction mixture was concentrated in vacuo. Toluene was added and concentrated again to remove excess reagent. The residue was purified by column chromatography on silica gel with a 1-10% ethyl acetate/n-hexane gradient mixture to give 24.9 g (0.50 mol 100%) of the title compound as a colorless oil.
Reaction SMILES: COC([N:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=3)(=[O:19])=[O:18])[CH:11]=2)[CH2:6]1)=O.Cl>C(O)C>[NH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[C:12]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:28])[F:29])[CH:21]=3)(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[CH2:6]1
Reactant: COC(=O)N1CCC(c2cccc(NS(=O)(=O)c3cccc(OC(F)(F)F)c3)c2)C1
Agent: Cl
Solvent: CCO
Product: O=S(=O)(Nc1cccc(C2CCNC2)c1)c1cccc(OC(F)(F)F)c1
Temperature: 120 °C
Yield: 48.5 %

Procedure:
3-[3-(3-Trifluoromethoxy-benzenesulfonylamino)-phenyl]-pyrrolidine-1-carboxylic acid methyl ester (0.105 g; 0.24 mmol) were dissolved in 2.5 ml ethanol and 0.9 ml of concentrated HCl were added. The reaction mixture was heated in a microwave system (CEM) at 90-150° C. for several hours until consumption of starting material. The mixture was then concentrated in vacuo and the acidic aqueous phase extracted twice with diethylether. The aqueous phase was adjusted to pH 9 with 1 N aqueous NaOH, extracted three times with diethylether, and the combined organic layers dried over sodium sulfate, filtered and the solvent evaporated to dryness to yield 45 mg of the product.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[CH3:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([CH3:30])[CH:29]=1)[CH2:25]Br>>[CH3:21][C:22]1[CH:29]=[C:28]([CH:27]=[C:24]([CH3:25])[CH:23]=1)[CH2:30][N:8]1[C:9]([S:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: Cc1cc(C)cc(CBr)c1
Product: Cc1cc(C)cc(Cn2c(Sc3cc(C)cc(C)c3)c(C(C)C)c(=O)[nH]c2=O)c1
Yield: 56.3 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3,5-dimethylbenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (230 mg, yield: 56.3%).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:16])[C:13](O)=[O:14])=[CH:8][CH:7]=1>>[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:16])[C:13]([Cl:3])=[O:14])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C(C)C(=O)O)cc1
Product: Cc1ccc(C(C)C(=O)Cl)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
160.65 g (1.35 mol) of thionyl chloride are placed in a 1 liter three-necked flask fitted with a mechanical stirrer and a condenser. 164.2 g (0.9 mol) of p-methylphenylpropionic acid are added little by little thereto at room temperature. After 4 hours, the reaction is terminated by heating at 60° C. for 1 hour. Excess SOCl2 is removed by distillation/n vacuo. In that manner 164.5 g of p-methylphenylpropionic acid chloride are obtained.
Reaction SMILES: [C:1]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)(=[O:4])[CH:2]=[CH2:3].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>O1CCOCC1>[N:21]1([CH2:3][CH2:2][C:1]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C=CC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Reactant: C1CCNCC1
Solvent: C1COCCO1
Product: O=C1Nc2cccnc2N(C(=O)CCN2CCCCC2)c2ccccc21

Procedure:
4.9 gm of 11-acryloyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one were after addition of 15 ml of piperidine, refluxed in 150 ml of dioxane for 2 hours. The solvent and excess amine were then distilled off in vacuo, and the residue was recrystallized from n-propanol.
Reaction SMILES: FC(F)(F)C(O)=O.[BH4-].[Na+].[N+:10]([C:13]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:17][C:14]=1[C:15]#[N:16])([O-:12])=[O:11].Cl>O1CCCC1>[N+:10]([C:13]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:17][C:14]=1[CH2:15][NH2:16])([O-:12])=[O:11]
Reactant: N#Cc1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: NCc1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 85 %

Procedure:
A mixture consisting of 2.4 ml of trifluoroacetic acid and 10 ml of tetrahydrofuran was added dropwise to a suspension of 1.2 g of sodium borohydride in 6 ml of tetrahydrofuran under ice-cooling. To the resulting mixture was added a solution of 1.48 g of 2-nitro-5-piperidinobenzonitrile which was prepared in Reference Example 1-(a) in 15 ml of tetrahydrofuran, followed by stirring overnight. 20 ml of a 10% hydrochloric acid aqueous solution was added dropwise to the reaction mixture under ice-cooling, and the resulting mixture was heat-refluxed for 1 hour. The tetrahydrofuran was removed from the reaction mixture by distillation under reduced pressure. The aqueous layer was washed with chloroform, neutralized with sodium hydrogencarbonate and extracted with chloroform. The extracted layer was washed with water, dried and concentrated to dryness under reduced pressure. Purification of the residue by silica gel chromatography gave 1.28 g of 2-nitro-5-piperidinobenzylamine as an oily substance.
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]1=[O:11].[CH3:12]I>C(Cl)(Cl)Cl>[CH3:12][O:11][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[N:1]=1
Reactant: CI
Reactant: O=c1ccc2c([nH]1)CCCC2
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(n1)CCCC2
Temperature: 25 °C

Procedure:
To a 0.33 M solution of 5,6,7,8-tetrahydroquinolin-2 (1H)-one in dry CHCl3 at room temperature was added 1.2 equiv of Ag2CO3 and 6 equiv of MeI. The final suspension was refluxed in the dark for 5 h. After allowing the reaction to cool to room temperature, the suspension was filtered through Celite and concentrated. The crude material was further purified by flash chromatography, eluting with a gradient from 100% hexanes to 10% EtOAc/hexanes to provide the title compound as a colorless oil.
Reaction SMILES: CN(C)C1C=CC=CC=1.[C:10]1([CH3:35])[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[C:18]1[C:19]([CH3:34])=[N:20][N:21]2[C:26](=O)[C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:24]([CH3:33])[NH:23][C:22]=12.P(Cl)(Cl)([Cl:38])=O>>[Cl:38][C:26]1[N:21]2[N:20]=[C:19]([CH3:34])[C:18]([C:11]3[C:12]([CH3:17])=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=3[CH3:35])=[C:22]2[N:23]=[C:24]([CH3:33])[C:25]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3c(C)cc(C)cc3C)c(C)nn2c1=O
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)c1c(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn2c1Cl
Yield: 61.4 %

Procedure:
Five droplets of N,N-dimethylaniline was added to a solution of ethyl 3-mesityl-2,5-dimethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-carboxylate (3 g, 8.49 mmol) in phosphorus oxychloride (80 g), followed by heating under reflux for four hours. The reaction mixture was added to ice and stirred for a while. Then, the mixture was extracted with ethyl acetate, and the organic layer was washed with an aqueous saturated solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (15-30% ethyl acetate/hexane), to give the title compound (1.94 g).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([I:26])[CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][N:10]([C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:17]([O:19][CH3:20])=[O:18])[C:9]2=[O:25])=O.S(Cl)(Cl)=O>CN(C=O)C>[C:2]([C:4]1[CH:5]=[C:6]([I:26])[CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][N:10]([C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:17]([O:19][CH3:20])=[O:18])[C:9]2=[O:25])#[N:1]
Reactant: COC(=O)c1ccc(C)c(-n2cnc3c(C(N)=O)cc(I)cc3c2=O)c1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C)c(-n2cnc3c(C#N)cc(I)cc3c2=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of methyl 3-[8-(aminocarbonyl)-6-iodo-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoate in DMF (15 ml) was added thionyl chloride (1.79 ml). The reaction mixture was stirred at room temperature for 30 minutes and ice-water added. The resultant mixture was extracted with methylene chloride (×2) and the combined organic layers washed with water, saturated NaHCO3 solution, dried (magnesium sulphate) and concentrated to yield methyl 3-(8-cyano-6-iodo-4-oxoquinazolin-3(4H)-yl)-4-methylbenzoate as a white solid (2.04 g); NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 3.88 (s, 3H), 7.61 (d, 1H), 8.03 (m, 2H), 8.53 (s, 1H), 8.67 (d, 1H), 8.74 (d, 1H); Mass Spectrum: M+H+ 446.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:10]=2)O1.Br[CH2:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]([O:33][CH3:34])[CH:28]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH3:34][O:33][C:29]1[CH:28]=[C:27]([CH2:26][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:10]=2)[CH:32]=[CH:31][N:30]=1
Reactant: COc1cc(CBr)ccn1
Reactant: CCOC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cc(Cc2ccnc(OC)c2)c2ccccc2n1
Temperature: 85 °C

Procedure:
In a microwave vial containing ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-2-carboxylate (K4) (0.23 g, 0.69 mmol), 4-(bromomethyl)-2-methoxypyridine (M3) (0.17 g, 0.83 mmol), and palladium tetrakis (0.52 g, 0.45 mmol) was, added 4.0 mL toluene, 2.8 mL, ethanol, and 1.0 mL 2.0 M aqueous Na2CO3. The resulting solution was heated to 85° C. for 30 minutes, filtered through Celite, and washed with excess ethyl acetate. The filtrate was washed twice with water, washed with brine, dried over sodium sulfate, filtered, and concentrated. The resultant residue was subjected to silica gel chromatography eluting with 0-100% ethyl acetate in hexanes to afford ethyl 4-[(2-methoxypyridin-4-yl)methyl]quinoline-2-carboxylate (M4) that gave a mass ion (ES+) of 323.3 for M+H+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][CH:12]([NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH2:11]3)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:34][CH2:35][CH2:36][S:37](Cl)(=[O:39])=[O:38].[H-].[Na+]>CN(C)C=O>[O:38]=[S:37]1(=[O:39])[CH2:36][CH2:35][CH2:34][N:1]1[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][CH:12]([NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH2:11]3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CC(C)S(=O)(=O)NC1Cc2ccc(-c3cccc(N)c3)cc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)S(=O)(=O)NC1Cc2ccc(-c3cccc(N4CCCS4(=O)=O)c3)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.2 %

Procedure:
A mixture of N-[5-(3-aminophenyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (100 mg, 0.30 mmol), and diisopropylethylamine (79 mg, 0.61 mmol), in dry dimethylformamide (2 ml) was treated with 3-chloropropanesulfonyl chloride (54 mg, 0.30 mmol) and stirred at room temperature for 1 h. Sodium hydride (60% dispersion in oil, 15 mg, 0.38 mmol) was added and the mixture stirred at 60° C. for 0.5 h. The reaction mix was cooled then partitioned between dichloromethane and 0.5M hydrochloric acid, and the organic layer was evaporated under reduced pressure to give a brown oil which was purified by column chromatography on a 5 g isolute silica sep-pak column eluting from 0-50% ethyl acetate in 40-60° C. petroleum ether to give the title compound as a yellow oil (12 mg, 9%).
Reaction SMILES: FC(F)(F)C([NH:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=O.C(N(CC)CC)C.[C:21](#[N:24])[CH:22]=[CH2:23]>C1COCC1>[C:21]([CH2:22][CH2:23][N:9]1[CH2:8][CH2:7][CH:6]([NH2:5])[CH2:11][CH2:10]1)#[N:24]
Reactant: C=CC#N
Reactant: O=C(NC1CCNCC1)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CCCN1CCC(N)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 29.9 %

Procedure:
A mixture of 3 g (15.3 mmol) of 4-trifluoroacetamidopiperidine, 3 g (4.25 mL, 30.6 mmol) of triethylamine, 3 mL (45.9 mmol) of acrylonitrile in 10 mL of THF was stirred at room temperature for 17 hr. The solvent and volatile were evaporated under reduced pressure. The residue was dissolved in 20 mL of methanol and 4 mL of 30% NH4OH and the solution was refluxed for 5 hr. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel eluting first with 500 mL of dichloromethane, then 500 mL of 0.5% methanol/dichloromethane, followed by 1000 mL of 9:1:0.1 dichloromethane/methanol/ammonium hydroxide to give 0.7 g (30% yield) of the N-(2-cyanoethyl)-4-aminopiperidine. Step 4: Preparation of 6-(2-chlorophenyl)-2-(N-2-cyanoethylpiperidyl-4-amino)-pyrido[2,3-d]-pyrimidin-7-ol
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.CC(C)([O-])C.[K+].[Si:18]([O:25][CH2:26][CH2:27][OH:28])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C1COCC1>[C:21]([Si:18]([O:25][CH2:26][CH2:27][O:28][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[F:1])([CH3:20])[CH3:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CC(C)(C)[Si](C)(C)OCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc([N+](=O)[O-])cc1F
Yield: 102.1 %

Procedure:
The same procedure detailed below for Compound 133 was used, but using 3,4-difluoronitrobenzene (225 mg, 1.4 mmol), potassium tert-butoxide (354 mg, 3.2 mmol) and 2-((tert-butyldimethylsilyl)oxy)ethan-1-ol (506 mg, 2.9 mmol) in THF (3 mL) to give the product (451 mg) after workup (yield assumed quantitative). The product was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].C(=O)([O-])[O-:16].[Na+].[Na+]>O.CC(C)=O>[OH:16][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(CBr)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1ccc(CO)c([N+](=O)[O-])c1
Yield: 95.7 %

Procedure:
4-Bromomethyl-3-nitrobenzoic acid (3.00 g, 11.5 mmol) and sodium carbonate (6.12 g, 57.7 mmol) were dissolved in water (40 mL) and acetone (40 mL). The reaction mixture was refluxed for 4 hours and then concentrated under reduced pressure to remove acetone. The residue was washed with diethyl ether three times. The aqueous layer was acidified with 6M hydrochloric acid, and then extracted with ethyl acetate three times. The combined organic layer was washed with water and brine, dried with sodium sulfate, filtered, concentrated under the reduced pressure. The residue was dried by means of a vacuum pump to give the desired product as brown solid (2.17 g, yield 95%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH2:10][CH2:9][C:8]=2[CH:12]=1)([O-])=O.[H][H]>CO.ClCCl.[Pd]>[O:11]1[C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:12][C:8]=2[CH2:9][CH2:10]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCO2
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc2c(c1)CCO2
Reaction time: 18 h
Yield: 97.3 %

Procedure:
To a suspension of 10.3 g (62.37 mmol) of 5-nitro-2,3-dihydrobenzofuran in 50 mL of MeOH and 10 mL of dichloromethane was added 350 mg of 10% palladium on carbon and the mixture was placed under 55 psi of hydrogen gas. Hydrogen gas uptake was evident during the first 30 minutes. After 18 hours, the mixture was then filtered through diatomaceous earth and concentrated to afford 8.2 g of 2,3-dihydrobenzofuran-5-ylamine as a gray solid which was used without further purification.
Reaction SMILES: C[Al](C)C.[I:5][C:6]1[C:7]([S:12]([NH2:15])(=[O:14])=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1.[CH3:16][O:17][C:18]1[N:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([NH:26][C:27](=O)[O:28]C)[N:19]=1>C1(C)C=CC=CC=1.ClCCl>[CH3:25][O:24][C:22]1[N:23]=[C:18]([O:17][CH3:16])[N:19]=[C:20]([NH:26][C:27](=[O:28])[NH:15][S:12]([C:7]2[C:6]([I:5])=[CH:11][CH:10]=[CH:9][N:8]=2)(=[O:13])=[O:14])[N:21]=1
Reactant: NS(=O)(=O)c1ncccc1I
Reactant: COC(=O)Nc1nc(OC)nc(OC)n1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1nc(NC(=O)NS(=O)(=O)c2ncccc2I)nc(OC)n1
Temperature: 0 °C

Procedure:
9.0 ml (18 mmol) of a 2M solution of trimethylaluminum in toluene are added dropwise at room temperature to 4.3 g (15 mmol) of 3-iodo-2-pyridinesulfonamide in 150 ml of dichloromethane. After evolution of gas has ceased, 3.85 [lacuna] (18 mmol) of methyl 4,6-dimethoxy-1,3,5-triazin-2-yl-carbamate in 20 ml of dichloromethane is added dropwise and the resulting solution is refluxed for 24 hours. The mixture is cooled and poured into 150 ml of ice-cold 1N hydrochloric acid. The organic phase is separated off and the aqueous phase is extracted 2× using dichloromethane. The organic phase is dried and evaporated. After triturating the crude product with diethyl ether, 3.1 g (44% of theory) of 3-(4,6-dimethoxy-1,3,5-triazin-2-yl)-1-(3-iodo-2-pyridylsulfonyl)urea of melting point 155° C. (dec.) are obtained.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:26]=O>C(O)(=O)C>[C:18]([N:17]1[CH2:16][CH2:15][C:12]2[C:11](=[CH:10][C:9]([C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:8])=[CH:14][CH:13]=2)[CH2:26]1)(=[O:20])[CH3:19]
Reactant: CC(=O)NCCc1ccc(C(=O)c2ccccc2)cc1
Reactant: C=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)N1CCc2ccc(C(=O)c3ccccc3)cc2C1
Temperature: 0 °C
Reaction time: 48 h
Yield: 34.8 %

Procedure:
N-[2-(4-Benzoylphenyl)ethyl]acetamide (16.46 mmol, 4.40 g) was introduced into glacial acetic acid (20 ml). Concentrated sulfuric acid (25 ml) and then formalin (49.29 mmol, 4.00 g) were slowly added thereto at 30° C. The mixture was stirred for 2 days and poured into ice-water, and the aqueous phase was extracted with ethyl acetate. The organic phase was washed with aqueous sodium carbonate solution, dried and concentrated. The residue was stirred with diethyl ether and the solid resulting therefrom was filtered off with suction. 1.6 g of the title compound were obtained as a beige-colored solid with a melting point of 110-113° C.
Reaction SMILES: N[CH2:2][C:3](=O)[CH2:4][CH2:5][C:6](O)=O.[CH3:10][O:11][C:12](=[O:19])[CH2:13][CH2:14][C:15]([CH2:17][NH2:18])=[O:16]>>[CH2:10]([O:11][C:12](=[O:19])[CH2:13][CH2:14][C:15]([CH2:17][NH2:18])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NCC(=O)CCC(=O)O
Reactant: COC(=O)CCC(=O)CN
Product: CCCCCCOC(=O)CCC(=O)CN

Procedure:
5-aminolevulinic acid (ALA) and 5-aminolevulinic acid methyl ester (ALA-Me) were purchased from Sigma. St. Louis, Mo. 5-aminolevulinic acid hexyl ester (ALA-Hex) was obtained from PhotoCure AS (Oslo, Norway).