Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1.B.C1COCC1.O.[OH-].[Na+]>FC(F)(F)C(O)=O.O1CCCC1>[CH2:1]1[CH:13]2[CH:5]([C:6]3[C:11]([NH:12]2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c3c([nH]c2c1)CCCC3
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c(c1)NC1CCCCC21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 79.1 %

Procedure:
1,2,3,4-Tetrahydrocarbazole (75 milligrams) was dissolved under nitrogen in 3 milliliters of trifluoroacetic acid. To the mixture, cooled in a water bath, was added dropwise about 1.5 milliliters of an about 1 M BH3.THF in tetrahydrofuran. The mixture was stirred at room temperature for about 45 minutes. Thereafter, water (1 milliliter) was added slowly and the resulting solution stirred for 10 minutes. The solution was then made basic with 10 percent aqueous sodium hydroxide, and the basic solution extracted with methylene chloride. The organic methylene chloride layer was washed once with saturated sodium chloride, dried over potassium carbonate, and evaporated in vacuo to obtain 60 milligrams (80 percent yield) of a crystalline 1,2,3,4,4a,9a-hexahydrocarbazole product, m.p., 93°-96° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[CH:10]1[CH2:18][C:17]2[NH:16][N:15]=[C:14]([CH3:19])[C:13]=2[C:12](=O)[CH2:11]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl.O>C(O)C>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[CH:10]1[CH2:18][C:17]2[NH:16][N:15]=[C:14]([CH3:19])[C:13]=2[C:12](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:11]1
Reactant: Cc1n[nH]c2c1C(=O)CC(c1cc(Cl)ccc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1n[nH]c2c1C(=NNC(=N)N)CC(c1cc(Cl)ccc1Cl)C2
Yield: 186.6 %

Procedure:
To a solution of 6-(2,5-dichlorophenyl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one hydrochloride (1.1 g), aminoguanidine hydrochloride (0.49 g) in ethanol (30 ml) were added concentrated hydrochloric acid (0.9 ml) and water (0.9 ml), and the mixture was refluxed for 5 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate, and the aqueous layer was concentrated under reduced pressure. Precipitated crystals were recrystallized from ethanol-water to give 6-(2,5-dichlorophenyl)-4-guanidinoimino-3-methyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 176) (1.2 g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19](=[O:22])[CH2:20][CH3:21])[CH2:10][C@@H:9]2[CH3:29])=[O:7])=[CH:4][CH:3]=1.C(O)(=O)CC.[CH:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH3:40][C:39]1[N:1]([C:2]2[CH:3]=[CH:4][C:5]([C:6]([N:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C@H:11]([N:18]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:19](=[O:22])[CH2:20][CH3:21])[CH2:10][C@@H:9]3[CH3:29])=[O:7])=[CH:30][CH:31]=2)[C:42]([CH3:41])=[CH:37][CH:38]=1
Reactant: c1ccccc1
Reactant: CCC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N)cc2)c2ccccc21
Solvent: CCC(=O)O
Product: CCC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(-n3c(C)ccc3C)cc2)c2ccccc21
Temperature: 25 °C
Yield: 80 %

Procedure:
(±)-Cis-N-{1-[4-(2,5-dimethyl-pyrrol-1-yl)-benzoyl]-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl}-N-phenyl-propionamide was prepared from (±)-cis-N-[1-(4-amino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide. A solution of (±)-cis-N-[1-(4-amino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide (150 mg, 0.36 mmol), and propionic acid (0.5 ml) in dry benzene (20 ml) was heated at reflux under argon in a flask equipped with a Dean-Stark trap while stirring with the exclusion of light. The resulting solution was cooled to room temperature, and concentrated under vacuum. Recovered oil was purified by silica gel chromatography, eluting with hexane-ethyl acetate (3:1) to give the title compound (140 mg, 80%).
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:15])(=[NH:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[N:27]=[C:28]=[S:29]>C1C=CC=CC=1.CCCCCC>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[NH:27][C:28]([NH:14][C:7](=[NH:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[S:29]
Reactant: CCCCCCC(=N)N
Reactant: FC(F)(F)c1ccc(Cl)c(N=C=S)c1
Agent: Cl
Agent: [Na]
Solvent: c1ccccc1
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CCCCCCC(=N)NC(=S)Nc1cc(C(F)(F)F)ccc1Cl

Procedure:
Following a procedure similar to that described in Example 42 but using 1.86 g. sodium in 250 ml. dry acetone, 13.4 g. heptanamidine hydrochloride, and 19.2 g. 2-chloro-5-(trifluoromethyl)phenyl isothiocyanate [prepared from 2-chloro-5-(trifluoromethyl)aniline] in 70 ml. acetone there was obtained 1-[2-chloro-5-(trifluoromethyl)phenyl]-3-(heptanimidoyl)-2-thiourea, m.p. 88°-90°C. (from benzene-n-hexane); hydrochloride (10.3 g.), m.p. 160°-161°C. (from acetonitrile).
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[CH3:7][CH:8]([CH3:25])[C:9]([O:11][CH2:12][CH2:13][O:14][C:15](ON1C(=O)CCC1=O)=[O:16])=[O:10]>>[CH3:2][N:1]([C:15]([O:14][CH2:13][CH2:12][O:11][C:9](=[O:10])[CH:8]([CH3:7])[CH3:25])=[O:16])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CNCC(=O)O
Reactant: CC(C)C(=O)OCCOC(=O)ON1C(=O)CCC1=O
Product: CC(C)C(=O)OCCOC(=O)N(C)CC(=O)O
Yield: 88.4 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, sarcosine (0.23 g, 2.63 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl 2-methylpropanoate (0.6 g, 2.1 mmol) were reacted to provide 0.459 g (85% yield) of the title compound (38) as a colorless liquid after work-up and mass-guided preparative HPLC purification. 1H NMR (CD3OD, 400 MHz): δ=6.88 (q, 1H), 4.12 (m, 2H), 2.9 (2s, 3H), 2.59 (m, 1H), 1.5-1.4 (2d, 3H), 1.1 (m, 6H). MS (ESI) m/z 270.06 (M+Na)+; 246.12 (M−H)−.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]#N)=[N:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:16].[Na+].[OH2:18]>CCO>[C:1]1([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:18])=[O:16])=[N:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccc(Nc2ccccc2)cn1
Reactant: [OH-]
Reactant: O
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1ccc(Nc2ccccc2)cn1
Yield: 87 %

Procedure:
A mixture of BINAP (0.167 g, 0.00027 mole), palladium acetate (0.06 g, 0.00027 mole) and toluene (10 mL) was degassed with argon for 15 minutes. This mixture was then added to a mixture of aniline (0.5 g, 0.00537 mole), 3-chloro-6-cyanopyridine (0.893 g, 0.00645 mole) and cesium carbonate (3.49 g, 0.01075 mole) in toluene (10 mL). The resulting mixture was heated to reflux for 22 hours. The reaction mixture was then concentrated under reduced pressure and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine solution, dried over sodium sulfate and concentrated under reduced pressure. Purification of the residue by column chromatography using silica gel 60-120 mesh (15% ethyl acetate in hexane) afforded 0.4 g (38%) of 5-phenylamino-pyridine-2-carbonitrile. To a stirred solution of 5-phenylamino-pyridine-2-carbonitrile (0.4 g, 0.00205 mol) in EtOH (15 mL) was added NaOH (0.246 g, 0.0061 mol) and water (10 mL) and the resulting mixture was heated to reflux for 4 hours. The mixture was then concentrated under reduced pressure and the residue was diluted with cold water. The resulting precipitate was isolated by filtration and dried to afford 0.385 g (87%) of 5-phenylamino-pyridine-2-carboxylic acid
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][C:18]3[N:19]=[C:20](Br)[S:21][C:22]=3[CH3:23])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)C.[CH3:26][CH2:27]O>C1COCC1.O>[CH:9]([C:26]1[CH:27]=[CH:7][C:6]([C:20]2[S:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[C@H:6]([CH2:5][C:4]([OH:3])=[O:25])[CH2:7][CH2:8]4)[N:19]=2)=[CH:5][CH:4]=1)([CH3:10])[CH3:8]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(Br)sc3C)ccc21
Reactant: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1sc(-c2ccc(C(C)C)cc2)nc1CCOc1ccc2c(c1)CC[C@H]2CC(=O)O
Reaction time: 24 h
Yield: 66 %

Procedure:
To a solution of Example 174 (305 mg, 0.657 mmol) in a mixture of THF (8 mL), water (8 mL), and EtOH (4 mL), was added LiON (63 mg, 2.63 mmol). The reaction mixture was vigorously stirred for 24 hours, diluted with water (20 mL), and washed with Et2O (10 mL). The aqueous phase was then acidified to pH ˜1 using 1 N HCl, and then extracted with CH2Cl2 (4×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was then purified by silica gel flash chromatography (95:5 CH2Cl2/MeOH) to afford product (189 mg, 66%) as a white solid. (C26H29NO3S): LC-MS, RT 3.95 min., M+H 436.4; 1H NMR (CDCl3): δ 1.25 (s, 3H), 1.28 (s, 3H), 1.70-1.82 (m, 1H), 2.32-2.43 (m, 2H), 2.45 (s, 3H), 2.74-2.98 (m, 4H), 3.18 (t, 2H), 3.47-3.54 (m, 1H), 4.28 (t, 2H), 6.72 (dd, 1H), 6.78 (s, 1H), 7.08 (d, 1H), 7.51 (AB quartet, 4H).
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([N:13]([CH3:45])[C:14]([N:16]([CH3:44])[C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29]([C@H:31]3[CH2:36][CH2:35][C@H:34]([NH:37][C:38](=[O:43])[O:39][CH2:40][CH2:41]Cl)[CH2:33][CH2:32]3)=[O:30])[CH2:18]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+]>CN(C=O)C.O>[F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([N:13]([CH3:45])[C:14]([N:16]([C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29]([C@H:31]3[CH2:36][CH2:35][C@H:34]([N:37]4[CH2:41][CH2:40][O:39][C:38]4=[O:43])[CH2:33][CH2:32]3)=[O:30])[CH2:18]2)[CH3:44])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN(C(=O)N(C)[C@@H]1CN(C(=O)[C@H]2CC[C@H](NC(=O)OCCCl)CC2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)N(C)[C@@H]1CN(C(=O)[C@H]2CC[C@H](N3CCOC3=O)CC2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of the compound (0.19 g) obtained in step 1 in DMF (5.0 mL) was added sodium hydride (0.022 g) at 0° C., and the mixture was stirred at room temperature for 4 days. The mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, water and saturated brine, dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 10→100% ethyl acetate/hexane) to give the title compound (0.12 g, 65%) as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21]Br)[CH:7]=1)[CH3:2].[CH3:24][C@H:25]1[C@@H:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:28][C:27](=[O:36])[NH:26]1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:26]2[C@@H:25]([CH3:24])[C@@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:28][C:27]2=[O:36])[CH:7]=1)[CH3:2]
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Reactant: CCOC(=O)Cc1cc(F)cc(Oc2ccc(Br)cc2CBr)c1
Product: CCOC(=O)Cc1cc(F)cc(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 7, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-5-fluoro-phenyl]-acetic acid ethyl ester and (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: N[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.O=[C:13]([CH2:17][CH2:18]C(O)=O)[C:14]([OH:16])=[O:15]>C(O)(=O)C.Cl.O>[C:17]1([CH2:13][C:14]([OH:16])=[O:15])[C:10]2=[C:11]3[C:6](=[CH:7][CH:8]=[CH:9]2)[CH2:5][CH2:4][CH2:3][N:2]3[CH:18]=1
Reactant: O=C(O)CCC(=O)C(=O)O
Reactant: NN1CCCc2ccccc21
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1cn2c3c(cccc13)CCC2
Yield: 42.9 %

Procedure:
17 g of 1-amino-1,2,3,4-tetrahydroquinoline (preparation see Example 1B) and 20 g of 2-ketoglutaric acid were heated under reflux at a temperature of 80° C. for 2 hours in a mixture of 160 ml of acetic acid and 11.4 ml of concentrated hydrochloric acid. To work up the reaction mixture the solid residue which remained was taken up in water and extracted with ethyl acetate. The organic phase was separated and extracted with 20% strength aqueous sodium hydroxide solution. The alkaline (pH=9) aqueous phase was separated and acidified to pH=4 by addition of aqueous 10% strength hydrochloric acid solution, and a precipitate formed. The solution was extracted with ethyl acetate. The organic phase was evaporated. 10.6 g of crude 5,6-dihydro- 4H-pyrrolo-[3,2,1-ij]quinoline-1-acetic acid were obtained as a solid residue.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:29])=[O:9])[CH:3]=1.C(NC(C)C)(C)C.[CH:37]1([CH2:40][NH:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[CH2:39][CH2:38]1>C(O)C>[CH:42]1([N:41]([CH2:40][CH:37]2[CH2:38][CH2:39]2)[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])(=[O:19])=[O:18])=[CH:13][C:12]=3[CH3:29])=[O:9])[CH:3]=2)[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]1
Reactant: C1CCC(NCC2CC2)CC1
Reactant: CCOC(=O)CCCNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Solvent: CC(C)NC(C)C
Solvent: CCO
Product: CCOC(=O)CCCNS(=O)(=O)c1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)c(C)c1
Temperature: 160 °C

Procedure:
A solution of ethyl 4-(4-(6-chloropyrimidine-4-carboxamido)-3-methylphenylsulfonamido)butanoate (Intermediate 35, 123 mg; 0.31 mmol) and diisopropylamine (105.5 mL; 0.61 mmol) in ethanol (4 ml) was treated with N-(cyclopropylmethyl)cyclohexanamine (56.6 mg, 0.4 mmol). The mixture was heated to 160° C. in a microwave for 1 hour and the solvent removed in vacuo. The residue purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give ethyl 4-(4-(6-(cyclohexyl(cyclopropylmethyl)amino)pyrimidine-4-carboxamido)-3-methylphenylsulfonamido)butanoate which was used directly without any further purification. The residue was dissolved in methanol (10 ml) and THF (10 ml) and treated with 5 N NaOH solution (1 ml). After stirring at RT for 5 hours the solvent was removed in vacuo. The residue was redissolved in water (10 ml) and acidified with concentrated HCl. The aqueous phase was extracted with EtOAc and the organic extracts passed through a hydrophobic frit and the solvent removed in vacuo. The residue was triturated with petroleum ether to yield the title compound as a white solid (120 mg, 73%).
Reaction SMILES: [O-]CC.[Na+].[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[CH2:14][C:15]#[N:16].[CH3:17][O:18][CH2:19][C:20](OCC)=[O:21].C(O)(=O)C>C(O)C.COCCOC>[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[CH:14]([C:20](=[O:21])[CH2:19][O:18][CH3:17])[C:15]#[N:16]
Reactant: N#CCc1cc(Cl)cc(Cl)c1Cl
Reactant: CCOC(=O)COC
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COCCOC
Solvent: CCO
Product: COCC(=O)C(C#N)c1cc(Cl)cc(Cl)c1Cl
Temperature: 0 °C

Procedure:
To a stirred refluxing solution of sodium ethoxide (from 1.38 g sodium) in ethanol (25 ml) was added over 5 minutes a mixture of 2,3,5-trichlorophenylacetonitrile (11 g) and ethyl methoxyacetate (8.85 g) in dry DME (25 ml). After 4 hours the mixture was cooled on ice and acidified by dropwise addition of acetic acid (ca. 6 ml), diluted with ice-water (150 ml) and extracted with dichloromethane (2×100 ml). The dichloromethane extract was washed with water, dried over MgSO4 and concentrated giving a yellow solid, which was triturated with a little ether and filtered. 8.6 g Homogeneous by TLC (19:1 CH2Cl2 :MeOH).
Reaction SMILES: C([C@@H]1C(OC)=[N:8][C@@H:7]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[N:21]=[CH:22][N:23](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:24]=2)[C:6]([O:44]C)=N1)(C)C.Cl.[OH:47][Li:48].O>C(O)C>[NH:23]1[CH:24]=[C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12][C@H:7]([NH2:8])[C:6]([O-:44])=[O:47])[N:21]=[CH:22]1.[Li+:48]
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1CCc1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: [Li]O
Agent: Cl
Solvent: CCO
Solvent: O
Product: N[C@@H](CCc1ccccc1-c1c[nH]cn1)C(=O)[O-]
Product: [Li+]
Temperature: 70 °C
Reaction time: 18 h
Yield: 82.2 %

Procedure:
(2R,5S)-2-isopropyl-3,6-dimethoxy-5-(2-(1-trityl-1H-imidazol-4-yl)phenethyl)-2,5-dihydropyrazine (87 mg, 0.146 mmol) was dissolved in ethanol (3 mL) and concentrated HCl (few drops) was added. The mixture was heated at 70° C. for 2 h and concentrated. The residue was taken up in MeOH/water (3:1, 4 mL) and LiOH.H2O (6 mg, 0.146 mmol) was added. The mixture was stirred at room temperature for 18 h and concentrated. The crude product was washed with dichloromethane, hexanes, suspended in methanol and filtered. The filtrate was concentrated to afford the desired product (30 mg, 0.120 mmol, 83%) as a white solid. 1H NMR (MeOH-d4): 0.84-1.00 (m, 2H), 1.86-1.94 (m, 1H), 2.77-2.85 (m, 1H), 4.26-4.28 (m, 1H), 7.10-7.19 (m, 3H), 7.23-7.28 (m, 1H), 7.41 (d, 1H, J=2.8 Hz), 7.64 (s, 1H).
Reaction SMILES: CS([C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[CH:12][C:11](=[O:14])[NH:10][C:8]=2[N:9]=1)=O.CS(C1N=C[C:22]2[CH:28]=[CH:27][C:26](=O)[NH:25][C:23]=2N=1)(=O)=O.[C:30](OCC)(=O)C>NC1C=CC=CC=1>[C:23]1([NH:25][C:4]2[N:5]=[CH:6][C:7]3[CH:13]=[CH:12][C:11](=[O:14])[NH:10][C:8]=3[N:9]=2)[CH:22]=[CH:28][CH:27]=[CH:26][CH:30]=1
Reactant: CS(=O)c1ncc2ccc(=O)[nH]c2n1
Reactant: CS(=O)(=O)c1ncc2ccc(=O)[nH]c2n1
Reactant: CCOC(C)=O
Solvent: Nc1ccccc1
Product: O=c1ccc2cnc(Nc3ccccc3)nc2[nH]1
Temperature: 25 °C

Procedure:
A suspension of 204 mg of the mixture of 2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one and 2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one in 1 mL of aniline was heated at reflux for 10 minutes resulting in a dark brown solution. Upon cooling to room temperature, a solid formed. Ethyl acetate was added, and the solid was collected by filtration, washed with ethyl acetate, then suspended in methanol and filtered, and washed with additional methanol to provide 175 mg of 2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one, mp>350° C.
Reaction SMILES: [CH2:1]([O:8][N:9]([C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([C:35](O)=[O:36])[CH2:24][CH2:23]1)[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N:40]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][N:9]([C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C@H:25]([C:35](=[O:36])[NH2:40])[CH2:24][CH2:23]1)[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CC[C@H]1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CC[C@H]1C(N)=O
Reaction time: 8 h
Yield: 86.5 %

Procedure:
A mixture of (2S,5R)-5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (8.56 g, 16 mmol), EDCI (3.2 g, 16 mmol), HOBt (2.2 g, 16 mmol), NH4Cl (1.7 g, 32 mmol), and DIPEA (4.0 g, 32 mmol) in dry DMF (40 mL) was stirred at it overnight. The mixture was diluted with EtOAc (300 mL), and washed with water (3×). The organic layer was dried over Na2SO4 and concentrated to give (2S,5R)-tert-butyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-2-carbamoyl-piperidine-1-carboxylate as yellow solid (7.4 g, 86%). ESI-MS (EI+, m/z): 557 [M+Na]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]#N.S(=O)(=O)(O)[OH:13].[CH2:17]([OH:19])[CH3:18]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([O:19][CH2:17][CH3:18])=[O:13]
Reactant: CCO
Reactant: N#CCc1c(F)cccc1Br
Reactant: O=S(=O)(O)O
Product: CCOC(=O)Cc1c(F)cccc1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 329 (3.89 g, 18.17 mmol) and concentrated sulfuric acid (35 mL) in ethanol (80 mL) was heated to reflux overnight. The mixture was allowed to cool down to room temperature, and poured into a mixture of ice/water, shaken for 15 min, and extracted with AcOEt. The extract was successively washed with water, sat. NaHCO3, water, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford title compound 330 (4.86 g, quantitative yield, contaminated) as a yellow oily liquid. LCMS: 261.0 and 263.0 (M+H)+.
Reaction SMILES: [Na].[CH:2]1([C:5](=[O:7])[CH3:6])[CH2:4][CH2:3]1.[C:8](OCC)(=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10].Cl>C(O)C.O>[CH:2]1([C:5](=[O:7])[CH2:6][C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)C1CC1
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=O)CC(=O)C1CC1
Temperature: 25 °C

Procedure:
Sodium metal (2.411 g, 105 mmol) was dissolved in ethanol (50 mL). The solution was heated to reflux followed by addition of a mixture of 1-cyclopropylethanone (8.4 g, 100 mmol) and diethyl oxalate (14.59 g, 100 mmol) dropwise over 30 minutes. The reaction mixture was heated at reflux for an additional 2 h, and then allowed to cool to room temperature over a 2 d period. The contents were diluted with water (200 mL) and acidified by dropwise addition of 6N HCl. The contents were extracted with EtOAc (3×75 mL), washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo. The final product was collected as 14.3 g (74%). LCMS E-S (M+H)=184.8 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.03 (d, J=7.83 Hz, 2 H) 1.13-1.19 (m, 2 H) 1.31 (t, J=7.07 Hz, 3 H) 1.81-1.90 (m, 1 H) 4.29 (q, J=7.16 Hz, 2 H) 6.43 (s, 1 H).