Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C@H:16]([C:26]([OH:28])=[O:27])[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]#[N:25])[CH:19]=1)=O)(C)(C)C>ClCCl>[C:24]([C:20]1[CH:19]=[C:18]([CH2:17][C@@H:16]([C:26]([OH:28])=[O:27])[NH2:15])[CH:23]=[CH:22][N:21]=1)#[N:25]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccnc(C#N)c1)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(C[C@H](N)C(=O)O)ccn1
Reaction time: 3 h
Yield: 95.1 %

Procedure:
Trifluoroacetic acid (10 ml) was added dropwise to a stirred, ice-cooled solution of N-t-butoxycarbonyl-3-(2-cyano-4-pyridyl)-(S)-alanine (Preparation 12; 1.6 g 5.5 mmol) in dichloromethane (10 ml) and the resulting solution stirred for 3 hours at the same temperature then evaporated under reduced pressure. The residue was dissolved in water (5 ml) and the pH of the solution adjusted to 7 with 1M aqueous sodium hydroxide solution before purification by ion-exchange chromatography on Bio Rad AG50W X-8 (H+ form) resin, using an elution gradient of pyridine:water (0:100 to 10:90), to give the title compound (1.0 g) as a white solid. Rf 0.17 (SS 13), m/e 192.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH2:26]([N:28]([CH2:38][CH3:39])[CH2:29][CH2:30][CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][NH:33]1)[CH3:27].C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH:32]1[CH2:31][CH2:30][CH2:29][N:28]([CH2:38][CH3:39])[CH2:26][CH3:27])=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CCN(CC)CCCC1CCCCN1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CCCC1CCCCN1C(=O)c1ccc(C(=O)NC(C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, 2-(3-diethylaminopropyl)piperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.09 minutes; C29H37Cl2N5O2 (558.55); mass spectrum: (M−H)−=558/560 (chlorine isotope).
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[CH:10]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([Cl:28])[CH:19]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][C:14](=O)[CH2:13]2)=[N:6][CH:7]=1.Cl.[CH3:31][O:32][NH2:33]>CO.N1C=CC=CC=1>[Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[CH:10]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[C:20]([Cl:28])[CH:19]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][C:14](=[N:33][O:32][CH3:31])[CH2:13]2)=[N:6][CH:7]=1
Reactant: CON
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)C2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CON=C1CCC(CC(C(=O)Nc2cnc(Br)cn2)c2ccc(S(C)(=O)=O)c(Cl)c2)C1
Temperature: 25 °C
Yield: 30.4 %

Procedure:
A solution of N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-propionamide (prepared as in Example 49, 190 mg, 0.38 mmol) and methoxyamine hydrochloride (48 mg, 0.57 mmol) in methanol (0.90 mL) and pyridine (0.90 mL) was heated under reflux for 3 h. The reaction mixture was allowed to cool to 25° C. and then was concentrated in vacuo. The resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic layers were washed with a 1N aqueous hydrochloric acid solution (50 mL) and a saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 50% ethyl acetate/hexanes) afforded the N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-methoxyimino-cyclopentyl)-propionamide (61.2 mg, 78%) as a yellow foam: mp 91–97° C.; (ES)+-HRMS m/e calcd for C20H22BrClN4O4S (M+H)+ 529.0307 found 529.0310.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:30])[N:13]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=3)[C:14](=[O:21])[C:15]=2[C:16]([O:18]CC)=[O:17])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(O)C.Cl>O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]([CH3:30])[N:13]([C:22]3[CH:23]=[CH:24][C:25]([C:28]#[N:29])=[CH:26][CH:27]=3)[C:14](=[O:21])[C:15]=2[C:16]([OH:18])=[O:17])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)n(C)n(-c2ccc(C#N)cc2)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cn1c(-c2ccc(C(C)(C)C)cc2)c(C(=O)O)c(=O)n1-c1ccc(C#N)cc1
Temperature: 25 °C
Yield: 38 %

Procedure:
A mixture of 34.5 g of 3-(4-t-butylphenyl)-1-(4-cyanophenyl)-4-ethoxycarbonyl-2-methyl-2H-pyrazol-5-one, 23.6 g of potassium carbonate, 621 ml of ethanol and 69 ml of water was refluxed under heating for 9 hours. The reaction solution was cooled to room temperature and adjusted to pH 1-2 with dilute hydrochloric acid. The resulting crystals were collected by filtration and dried under reduced pressure. The resulting crude crystals were recrystallized in methanol-ethyl acetate to give 12.2 g of the title compound as colorless crystals. The mother liquor was concentrated, and the resulting residue was crystallized in chloroform-diethyl ether to give 8.3 g of the title compound as pale yellow crystals.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[NH:17][C:18](=[O:20])[CH3:19])[CH2:4][CH2:3]1.[H-].[Na+].[CH3:23]I.[Cl-].[NH4+]>CN(C=O)C>[CH3:23][N:17]([C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[C:18](=[O:20])[CH3:19]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1N1CCN(C)CC1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1cc([N+](=O)[O-])ccc1N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of N-[2-(4-methylpiperazin-1-yl)-5-nitrophenyl]acetamide (433 mg) and DMF (5 mL), 63% sodium hydride in oil (66 mg) was added under ice cooling and stirred at room temperature for 1 hour. The reaction liquid was ice cooled again, and methyl iodide (0.11 mL) was added and stirred at room temperature for 4 hours. The reaction liquid was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol) to give N-methyl-N-[2-(4-methylpiperazin-1-yl)-5-nitrophenyl]acetamide (200 mg) as an orange solid.
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][N:26]3[N:30]=[CH:31][CH:32]=[C:25]23)[CH2:6]1)(=O)C.C[O-].[Na+].C(O)(=O)C>CO.O1CCCC1>[SH:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[O:11])[C@H:7]([CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][N:26]3[N:30]=[CH:31][CH:32]=[C:25]23)[CH2:6]1
Reactant: CC(=O)S[C@H]1C[C@@H](CN2CCCn3nccc32)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](S)C[C@H]1CN1CCCn2nccc21
Reaction time: 0.25 h
Yield: 89.2 %

Procedure:
To a solution of (2S,4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl) -2-{4,5,6,7-tetrahydropyrazolo [1,5-a]pyrimidin-4-yl}methylpyrrolidine (2.22 g) in a mixture of methanol (40 ml) and tetrahydrofuran (20 ml) was added 28% sodium methoxide in methanol solution (0.98 ml) under ice-cooling and the mixture was stirred at the same temperature for 15 minutes. To the reaction mixture was added acetic acid (0.29 ml) at the same temperature and the mixture was evaporated in vacuo. The resulting residue was dissolved in a mixture of ethyl acetate (100 ml) and water (30 ml). The organic layer was separated and washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of chloroform and methanol (19:1, V/V). The fractions containing the desired compound were collected and concentrated in vacuo to give (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl) -2-{4,5,6,7-tetrahydropyrazolo[ 1,5-a]pyrimidin-4-yl}methylpyrrolidine (1.80 g).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[NH:8][C:7](=[O:9])[C:6]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[N:5]=1.[NH2:15][C:16]1[S:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[C:17]=1[C:25](O)=[O:26].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C>[NH2:15][C:16]1[S:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[C:17]=1[C:25]([N:12]1[CH2:13][CH2:14][C:6]2([N:5]=[C:4]([CH2:3][S:2][CH3:1])[NH:8][C:7]2=[O:9])[CH2:10][CH2:11]1)=[O:26]
Reactant: CSCC1=NC2(CCNCC2)C(=O)N1
Reactant: Nc1sc2ccccc2c1C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CSCC1=NC2(CCN(C(=O)c3c(N)sc4ccccc34)CC2)C(=O)N1

Procedure:
A solution of 3A (1.0 equivalent) in DMF (0.12 M) along with a 2-aminobenzo[b]thiophene-3-carboxylic acid (1.0 equivalent) was treated with EDC (1.0 equivalent), HOBt (1.0 equivalent) and Et3N (2.0 equivalents) at rt. The reaction mixture was stirred until the reaction was complete as determined by LCMS analysis and then partitioned between ethyl acetate and water. Organic layers were washed with brine and dried over Na2SO4, and volatiles removed under reduced pressure. Residue purified by LCMS to afford 8-(2-aminobenzo[b]thiophene-3-carbonyl)-2-(methylthiomethyl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one (2B).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7]4=[C:8]([C:17](=[O:20])[NH:18][N:19]=[C:6]4[C:5]=2[CH:4]=1)[CH:9]=[CH:10][CH:11]=3.[CH2:21]([O:28][P:29]([CH2:39][CH2:40]C(O)=O)([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:32]([O:31][P:29]([CH2:39][CH2:40][O:1][CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7]4=[C:8]([C:17](=[O:20])[NH:18][N:19]=[C:6]4[C:5]=2[CH:4]=1)[CH:9]=[CH:10][CH:11]=3)(=[O:30])[O:28][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=c1[nH]nc2c3c(cccc13)Oc1ccc(CO)cc1-2
Reactant: O=C(O)CCP(=O)(OCc1ccccc1)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=c1[nH]nc2c3c(cccc13)Oc1ccc(COCCP(=O)(OCc3ccccc3)OCc3ccccc3)cc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a solution of compound 57 (0.5 mmol) in anhydrous DMF was added 3-bis(benzyloxy)phosphorylpropanoic acid (0.75 mmol) and EDC (0.75 mmol) and DMAP (catalytic amount). The reaction mixture was stirred at room temperature overnight. Solvent was removed in vacuo. To the residue, 100 mL ethyl acetate was added. The organic layer was washed with water, and dried with MgSO4. Solvent was removed to afford a colorless oil, which was recrystallized in EtOAc/Hexanes to afford a white solid 58 in 40% yield. MS (ES−): 581; Mp: 173-175° C. 1H-NMR (CDCl3, 400 MHz): 10.01 (s, 1H), 8.11 (d, J=2.0 Hz, 1H), 8.07 (d, J=7.5 Hz, 1H), 7.82 (t, J=8.5 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.40 (dd, J=8.5 and 2.0 Hz, 1H), 7.35-7.22 (m, 11H), 5.09 (s, 2H), 4.98 (m, 4H), 2.62 (m, 2H), 2.12 (m, 2H); Anal: Calcd for C32H27N2O7P: C, 65.98; H, 4.67; N, 4.81. Found: C, 65.69; H, 4.82; N, 5.09.
Reaction SMILES: [O:1]=[C:2]1[NH:9][CH:8]=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:6]=[C:3]1C#N.S(=O)(=O)(O)O.[OH-].[NH4+].N1C=CC(C2C=CC(=O)NC=2)=CC=1.[N+:36]([O-])([OH:38])=[O:37]>O>[N+:36]([C:3]1[C:2](=[O:1])[NH:9][CH:8]=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:6]=1)([O-:38])=[O:37]
Reactant: O=[N+]([O-])O
Reactant: N#Cc1cc(-c2ccncc2)c[nH]c1=O
Agent: O=S(=O)(O)O
Agent: O=c1ccc(-c2ccncc2)c[nH]1
Agent: [NH4+]
Solvent: O
Product: O=c1[nH]cc(-c2ccncc2)cc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
Alternatively, 3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone is prepared step-wise starting with 1,2-dihydro-2-oxo-5-(4-pyridinyl)-nicotinonitrile as follows: A mixture containing 197 g. of 1,2-dihydro-2-oxo-5-(4-pyridinyl)-nicotinonitrile, 600 ml. of concentrated sulfuric acid and 150 liters of water was refluxed for twenty-four hours, cooled and poured into 10 liters of a mixture of ice and water. The mixture was neutralized with ammonium hydroxide and the separated precipitate was collected, washed with a small amount of cold water and dried in vacuo at 80° C. to yield 148 g. of 5-(4-pyridinyl)-2(1H)-pyridinone, m.p. 258°-260° C. An 80 g. portion of 5-(4-pyridinyl)-2(1H)-pyridinone was added to 288 ml. of concentrated sulfuric acid and the mixture heated to 70° C. To this stirred solution kept at 70°-80° C. was added dropwise a mixture containing 102 ml. of 90% nitric acid and 29 ml. of concentrated sulfuric acid. The reaction mixture was heated at about 80° C. for three hours after addition of the mixture of acids. The reaction mixture was then cooled and poured into a mixture of ice and water with stirring. The precipitate was collected and dried. It was then slurried with water and neutralized with 10% aqueous potassium bicarbonate solution. The precipitate was collected, washed with water and dried in vacuo at 80° C. to yield 56 g. of 3-nitro-5-(4-pyridinyl)-2(1H)-pyridonone.
Reaction SMILES: C(O)CCO.C(C=C)=O.[C:10]1([CH3:20])[CH:15]=CC(S(O)(=O)=O)=C[CH:11]=1.[CH:21]([CH:23]1[O:28]CCC[O:24]1)=[CH2:22]>O>[CH:21]([CH:23]1[O:28][CH2:11][CH:10]([CH3:20])[CH2:15][O:24]1)=[CH2:22]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C=CC1OCCCO1
Agent: C=CC=O
Solvent: OCCCO
Solvent: O
Product: C=CC1OCC(C)CO1
Temperature: 26 °C

Procedure:
For the sake of comparison, a mixture of 0.5 mole 1,3-propanediol and 0.55 mole acrolein were reacted at 50° C in the presence of 0.3 g. p-toluenesulfonic acid. Layers did not separate until the reaction mixture was cooled to 26° C. The mixture gave 18 g. of an aqueous layer which contained about 40% diol, 21% acrolein, 10% 2-vinyl-1,3-dioxane and 25% water. The acetal layer of 49 g. contained 63% 2-vinyl-1,3-dioxane, 23% acrolein, 8% diol and 5% water, conversion to acetal was about 60% which represents only a negligible increase over equilibrium conversion.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[S:11][C:10]([Br:12])=[N:9][C:8]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])=O)[CH:2]=[CH2:3].P(Cl)(Cl)(Cl)(Cl)Cl.Cl.O1CCOCC1.CO[CH:36](OC)[CH2:37][NH2:38]>ClCCl.O>[CH2:1]([N:4]1[CH:36]=[CH:37][N:38]=[C:5]1[C:7]1[S:11][C:10]([Br:12])=[N:9][C:8]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH:2]=[CH2:3]
Reactant: COC(CN)OC
Reactant: C=CCNC(=O)c1sc(Br)nc1-c1ccc(Cl)cc1Cl
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: C=CCn1ccnc1-c1sc(Br)nc1-c1ccc(Cl)cc1Cl
Temperature: 60 °C
Yield: 66.8 %

Procedure:
To a solution of N-Allyl-2-bromo-4-(2,4-dichlorophenyl)-1,3-thiazole-5-carboxamide (8.40 g, 21.4 mmol) in dichloromethane (200 mL) was added phosphorus pentachloride (5.05 g, 24.2 mmol) and 4M hydrochloric acid in dioxane (0.833 mL, 3.26 mmol), and the reaction was heated to 60° C. for 90 minutes under an atmosphere on nitrogen. The reaction was allowed to cool to room temperature and then aminoacetaldehyde dimethyl acetal (25.7 mL, 236 mmol) was added slowly through the condenser. The mixture was heated to 60° C. for 2 hours under an atmosphere on nitrogen. The mixture was cooled to room temperature, and water was added (200 mL). The layers were separated and the organic phase was washed with water again (2×200 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and washed with dichloromethane (200 mL). To this dichloromethane solution of the intermediate was added 4M hydrochloric acid in dioxane (17 mL, 65 mmol) and the solution was stirred at reflux for 16 hours. The solution was decanted (leaving behind an oily black residue on the flask) and then evaporated and diluted with ethyl acetate and saturated sodium bicarbonate solution. The layers were separated and the aqueous phase was extracted 3 more times with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield the title compound (5.93 g, 67%). LCMS: (FA) ES+, 416. 1H NMR (400 MHz, d1-chloroform) δ: 7.45-7.42 (m, 1H), 7.25-7.19 (m, 2H), 7.16-7.14 (m, 1H), 6.93-6.90 (m, 1H), 5.55-5.44 (m, 1H), 5.13-5.08 (m, 1H), 5.95-4.88 (m, 1H), 4.19-4.15 (m, 2H).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]12.[NH:19]1[CH:23]=[CH:22][N:21]=[N:20]1.CN(C)[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[Cu]I.O>[N:19]1[N:20]([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][N:6]2[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]23)[N:21]=[CH:22][CH:23]=1
Reactant: c1c[nH]nn1
Reactant: O=C1C=C2c3cccc(I)c3CCN2C(=O)CN1
Agent: [Cu]I
Agent: CN(C)[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C=C2c3cccc(-n4nccn4)c3CCN2C(=O)CN1
Temperature: 130 °C
Reaction time: 0.07 h
Yield: 19.4 %

Procedure:
136-1. A mixture of 9-iodo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (600 mg, 1.69 mmol), 1H-1,2,3-triazole (421 mg, 6.10 mmol), trans-N,N-dimethylcyclohexane-1,2-diamine (87 mg, 0.61 mmol), cesium carbonate (1987 mg, 6.10 mmol) and CuI (323 mg, 1.69 mmol) in DMF (6 mL) were heated under Ar at 130° C. in the microwave for 5 hr. The mixture was cooled to rt. Water was added and the mixture was extracted with CH2Cl2 (2×). The combined organic layers were dried with sodium sulfate and evaporated under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera Four, eluent: DCM for 4 min, then from 0% MeOH in DCM to 5% MeOH in DCM in 26 min, followed by 5% MeOH in DCM for 5 min) to yield the title compound as yellow oil (97 mg). UPLC-MS: MS 296.2 (M+H+); UPLC rt 0.63 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[N+:11]([C:14]1[CH:15]=[C:16]([S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20])[S:17][CH:18]=1)([O-:13])=[O:12]>C(#N)C>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:23]([NH:22][S:19]([C:16]2[S:17][CH:18]=[C:14]([N+:11]([O-:13])=[O:12])[CH:15]=2)(=[O:21])=[O:20])=[O:24])[N:7]=1
Reactant: O=C=NS(=O)(=O)c1cc([N+](=O)[O-])cs1
Reactant: COc1cc(C)nc(N)n1
Solvent: CC#N
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cc([N+](=O)[O-])cs2)n1
Temperature: 25 °C

Procedure:
To 1.4 g of 2-amino-4-methoxy-6-methylpyrimidine in 25 ml of anhydrous acetonitrile was added 2.4 g of 4-nitrothiophene-2-sulfonyl isocyanate with stirring at ambient temperature. After stirring for sixteen hours, the mixture was filtered and the precipitate washed with 1-chlorobutane. It melted at 155° with decomposition and showed an infrared absorption spectrum with peaks at 1700, 1620 and 1570 cm-1 consistent for the desired structure.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[CH2:10][CH2:11][N:12]=[C:13]=[O:14]>C(Cl)Cl.C(N(C(C)C)CC)(C)C.CCOC(C)=O>[I:1][C:2]1[CH:3]=[C:4]([N:5]2[CH2:10][CH2:11][NH:12][C:13]2=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(I)c1
Reactant: O=C=NCCCl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NCCN1c1cccc(I)c1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
A solution of 3-iodoaniline (1 g) in CH2Cl2 (5 ml) and diisopropylethylamine (2 ml) was treated with 2-chloroethylisocyanate (0.4 ml) and the mixture was stirred at 20° C. for 3 d. The mixture was diluted with EtOAc and washed with 2M HCl, dried and evaporated to dryness. The residue was dissolved in DMF (5 ml), treated with sodium hydride (60% oil dispersion, 182 mg), and the mixture was stirred for 20 h under nitrogen. The mixture was diluted with EtOAc, washed with 2M HCl, brine, dried and evaporated to dryness. The residue was crystallised from hot EtOAc/MeOH. Trituration in Et2O of the residue obtained by evaporation of the mother liquor gave the title compound (240 mg). LCMS RT=3.03 min.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][Br:10])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[N+:11]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O)([O-:13])=[O:12].C(O)(=O)C.N1CCCCC1>C(O)(C)C>[N+:11]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[C:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH2:8][CH2:9][Br:10])=[O:6])([O-:13])=[O:12]
Reactant: CC(=O)CC(=O)OCCBr
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCCBr

Procedure:
405 g of 2-bromoethyl acetoacetate are dissolved in 1500 ml of isopropanol. 293 g of 3-nitrobenzaldehyde, 4.6 g of acetic acid and 6.8 g of piperidine are added while stirring. The mixture is stirred at 40° C. until a clear solution has formed. The solution is allowed to cool slowly, seeded with a few crystals of the title compound and stirred at room temperature for 48 h and then cooled, and the product is filtered off under suction, washed with cold isopropanol and dried in vacuo at 50° C. 495 g of the title compound of m.p. 94.5°-95.5° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].CN(C(ON1N=[N:58][C:53]2[CH:54]=[CH:55][CH:56]=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C1(CN)CC1>CN(C=O)C>[CH:54]1([CH2:53][NH:58][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:27]([CH3:28])=[C:19]([C:18]3[C:13]4[CH:12]=[CH:11][C:10](=[O:42])[N:9]([C:3]5[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=5[F:8])[C:14]=4[N:15]=[C:16]([N:29]4[CH2:34][CH2:33][CH:32]([N:35]5[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]5)[CH2:31][CH2:30]4)[N:17]=3)[CH:20]=2)[CH2:56][CH2:55]1
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCC1CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NCC2CC2)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and 1-cyclopropylmethanamine (7.15 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (6.2 mg, 18%). LC-MS m/z 627 (M+H)+.