Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)O)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](#[N:21])[CH2:18][C:19]#[N:20].C(N(CC)CC)C>CN(C=O)C>[NH2:21][C:17]1[O:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:18]=1[C:19]#[N:20]
Reactant: N#CCC#N
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1c(N)oc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Stir 100 g (470 mmol) of benzoin, 62.25 g (940 mmol) of malononitrile and 47.68 g (470 mmol) of triethylamine at RT in 1345 ml of DMF overnight. Add a further 41 g (620 mmol) of malononitrile and stir the mixture at RT for another 24 h. Then add ethyl acetate and water and extract the aqueous phase twice with ethyl acetate. Dry the combined organic phases over magnesium sulphate and concentrate them under reduced pressure. After column chromatography on silica gel (eluent: dichloromethane→dichloromethane/methanol 98:2), 120 g (97.9% of theory) of the title compound are obtained as yellowish solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[C:16]([O-:19])([O-])=O.[K+].[K+].[CH3:22][N:23]([CH:25]=[O:26])C>O>[C:9]1(=[O:10])[N:5]([CH2:4][CH2:3][CH2:2][O:19][C:16]2[CH:12]=[CH:13][CH:14]=[C:7]3[C:8]=2[CH:9]=[CH:22][N:23]=[C:25]3[OH:26])[C:6](=[O:15])[C:7]2=[CH:14][CH:13]=[CH:12][CH:11]=[C:8]12
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [K+]
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCOc1cccc2c(O)nccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-(3-Bromopropyl)phthalimide (164 g) is added to a stirred solution of 5-hydroxy-1,2-dihydro-1-(2H)-isoquinolone (96.7 g) and anhydrous K2CO3 (91.2 g) in 750 ml of DMF. The reaction mixture is stirred at room temperature for one week, diluted with 3 liters of H2O and stirring continued at RT for an additional 30 minutes. The reaction mixture is filtered and the solid resuspended in 2 liters of H2O and stirred at RT for an additional 11/2 hours. The suspension is filtered and the solid dried in air. The dried solid is broken up, suspended in 750 ml of chloroform and stirred vigorously at RT for 1 hour. The suspension is filtered and the solid dried. The crude product (95.8 g) is dissolved in 2.5 liters in boiling glacial acetic acid. The resulting dark solution is concentrated and cooled. The crystalline precipitate is collected and dried, washed with diethyl ether, resuspended in diethyl ether, stirred at RT for 30 minutes, filtered and dried in vacuo overnight, yielding 59.3 g of the desired product, M.P.>300° C.
Reaction SMILES: [C:1]1([C:11]2[NH:12][C:13]3[C:18]([N:19]=2)=[C:17]([O:20][C@H:21]2[CH2:25][CH2:24][C@H:23]([CH2:26][OH:27])[CH2:22]2)[N:16]=[CH:15][N:14]=3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl[S:29]([NH2:32])(=[O:31])=[O:30]>CC(N(C)C)=O.CC#N>[S:29](=[O:31])(=[O:30])([O:27][CH2:26][C@H:23]1[CH2:24][CH2:25][C@H:21]([O:20][C:17]2[N:16]=[CH:15][N:14]=[C:13]3[C:18]=2[N:19]=[C:11]([C:1]2[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=2)[NH:12]3)[CH2:22]1)[NH2:32]
Reactant: NS(=O)(=O)Cl
Reactant: OC[C@H]1CC[C@H](Oc2ncnc3[nH]c(-c4cccc5ccccc45)nc23)C1
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: NS(=O)(=O)OC[C@H]1CC[C@H](Oc2ncnc3[nH]c(-c4cccc5ccccc45)nc23)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a solution of ((1S,3S)-3-{[8-(1-naphthyl)-9H-purin-6-yl]oxy}cyclopentyl)-methanol (66.1 mg, 0.000183 mol) in DMA (8.12 mL) at 0° C. was added chlorosulfonamide (106 mg, 0.00091.7 mol) in CH3CN (2.0 mL). The reaction was stirred at 0° C. for 10 mins, then 23° C. for 3 hours. The reaction was quenched with water and extracted with EtOAc (3×). The combined organics were washed with water (2×), dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography (0 to 6% MeOH/CH2Cl2) to obtain 56.3 mg (70%) of the title compound as a white solid. 1H NMR (CD3OD, 400 MHz) δ: 8.52-8.48 (m, 2H), 8.10-8.07 (m, 111, 8.01-7.98 (m, 1H), 7.90-7.87 (m, 1H), 7.65-7.57 (m, 3H), 5.89-5.85 (m, 1H), 4.12-4.07 (m, 2H), 2.75-2.66 (m, 1H), 2.30-2.21 (m, 2H), 2.16-2.01 (m, 2H), 1.93-1.85 (m, 1H), 1.62-1.53 (m, 1H) ppm. LC/MS: Rt=1.38 min, ES+ 442 (FA standard).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9](=[O:39])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:18]=[CH:19][C:20]4[N:26]([CH3:27])[C:25](=[O:28])[C:24]([F:30])([F:29])[CH2:23][N:22]([CH:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[C:21]=4[N:36]=3)=[C:12]([O:37][CH3:38])[CH:11]=2)[CH2:3][CH2:2]1.[CH3:40]I>>[CH:31]1([N:22]2[CH2:23][C:24]([F:30])([F:29])[C:25](=[O:28])[N:26]([CH3:27])[C:20]3[CH:19]=[N:18][C:17]([NH:16][C:13]4[CH:14]=[CH:15][C:10]([C:9]([NH:8][CH:4]5[CH2:5][CH2:6][CH2:7][N:1]([CH3:40])[CH2:2][CH2:3]5)=[O:39])=[CH:11][C:12]=4[O:37][CH3:38])=[N:36][C:21]2=3)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COc1cc(C(=O)NC2CCCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CI
Product: COc1cc(C(=O)NC2CCCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized by methylating N-(Azepan-4-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamide using methyl iodide. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58-1.93 (m, 17 H) 2.28 (br. s., 3 H) 2.33 (br. s., 1 H) 3.93 (s, 3 H) 4.05 (t, J=14.0 Hz, 3 H) 4.75 (d, J=7.1 Hz, 1 H) 7.37-7.53 (m, 2 H) 7.96 (s, 1 H) 8.15 (d, J=7.8 Hz, 1 H) 8.26 (t, J=4.0 Hz, 2 H). [M+H] calc'd for C28H37F2N7O3, 558; found 558.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:9](Br)Br)=[N:4][C:5]([Br:8])=[CH:6][CH:7]=1.CC[OH:14]>O.[N+]([O-])([O-])=O.[Ag+]>[Br:1][C:2]1[C:3]([CH:9]=[O:14])=[N:4][C:5]([Br:8])=[CH:6][CH:7]=1
Reactant: Brc1ccc(Br)c(C(Br)Br)n1
Reactant: CCO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: O=Cc1nc(Br)ccc1Br
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A solution of silver nitrate (7.6 g, 45 mmol) in water (24 mL) was added dropwise to a solution of 42A (7.36 g, 18 mmol) in refluxing EtOH (90 mL). The mixture was stirred at 80° C. for 5 hours. After the mixture was cooled to room temperature, it was diluted with water (100 mL), extracted with EtOAc (3 times), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product (42B, 4.6 g) was directly used for next step. MS (m/z): 265.96. [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:29])[NH:10][CH:11]2[C:17](=[O:18])[NH:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[CH:13]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:12]2)[CH:5]=[CH:6][CH:7]=1.[C:30]([NH:34][C:35](=[O:38])[CH2:36]I)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([NH:34][C:35](=[O:38])[CH2:36][N:16]1[C:17](=[O:18])[CH:11]([NH:10][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[O:29])[CH2:12][CH:13]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]1=2)([CH3:33])([CH3:32])[CH3:31]
Reactant: O=C(Nc1cccc(Cl)c1)NC1CC(C2CCCCC2)c2ccccc2NC1=O
Reactant: CC(C)(C)NC(=O)CI
Product: CC(C)(C)NC(=O)CN1C(=O)C(NC(=O)Nc2cccc(Cl)c2)CC(C2CCCCC2)c2ccccc21
Yield: 59 %

Procedure:
Following the previous expermental procedure, 3-[3-(3-chloro-phenyl)-ureido]-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-benzo[b]azepine (0.4 g, 1 mmol) was alkylated with N-tert.-butyl iodoacetamide (0.28 g, 1.2 mmol) to provide the title compound as a white solid, 0.3 g, 59% yield. mp 222-5° C. 1H NMR (CDCl3) δ 8.03 (s, 1), 7.59 (t, 1), 7.34-7.15 (m, 3), 7.10 (d, 1),7.01 (t, 1), 6.91 (d, 1), 6.83 (d, 1), 6.43 (bd, 1), 6.43 (bd, 1), 6.31 (s, 1), 4.95 (d, 1), 4.54 (m, 1), 3.59 (d, 1), 2.66 (m, 1), 2.53 (t, 1), 2.18 (bd, 1), 1.78 (m, 1), 1.59 (m, 1), 1.4 (s, 9), 1.29-0.78 (m, 6), 0.58 (m, 1).
Reaction SMILES: [CH2:1]=[C:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][C:6](=[O:14])[CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH3:19]COCC>>[OH:14][C:6]1([CH3:19])[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:2](=[CH2:1])[C:3]2[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=2[CH2:5]1
Reactant: C=C1c2ccccc2CC(=O)Cc2ccccc21
Reactant: CCOCC
Product: C=C1c2ccccc2CC(C)(O)Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Upon completion of the addition, the mixture was heated at reflux for one hour, then cooled to room temperature. A solution of 15.1 g. (0.065 mole) of 12-methylene-6-oxo-5,6,7,12-tetrahydrodibenzo[a,d]cyclooctene in 100 ml. of ether was added over 5 minutes to the stirred Grignard solution, and the resulting mixture was stirred for one hour at room temperature and quenched in 1 liter of ice water containing 5 g. of ammonium chloride. The resulting suspension was extracted three times with ether (200 ml.), and the combined ether layers were washed once with dilute aqueous sodium bisulfite, once with dilute sodium bicarbonate, and twice with water. The washed ether solution was dried over potassium carbonate, filtered, and evaporated in vacuo to give 6-hydroxy-6-methyl-12-methylene-5,6,7,12-tetrahydrodibenzo[a,d]cyclooctene as a colorless oil, 17.7 g.
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([O:8][C:9]([N:11]1[CH2:17][C:16](=O)[C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>C(N(CC)CC)C>[C:4]([O:8][C:9]([N:11]1[CH2:17][C:16](=[N:2][OH:3])[C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CC(=O)C2(CC2)C1
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(=NO)C2(CC2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.4 %

Procedure:
1.25 g of hydroxylamine hydrochloride and 1.8 g of triethylamine were added to a solution of 1.9 g of compound 66. The mixture was stirred at room temperature for 1 day. The solvent was removed under reduced pressure and 10% citric acid aqueous solution was added to the residue. The mixture was extracted with chloroform and the extract was washed with water. The extract was dried and the solvent was removed under reduced pressure to yield 1.86 g of title compound 67.
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].[N+:7]([C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13])([O-:9])=[O:8]>CCCCCC.O1CCCC1>[N+:7]([C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]([OH:13])[C:2]#[C:1][Si:3]([CH3:6])([CH3:5])[CH3:4])([O-:9])=[O:8]
Reactant: C#C[Si](C)(C)C
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si](C)(C)C#CC(O)c1ccccc1[N+](=O)[O-]
Temperature: -76 °C
Reaction time: 0.5 h

Procedure:
Into a round-bottomed flask was placed ethynyltrimethylsilane (4.90 mL), and tetrahydrofuran (THF) and was cooled to −76° C. A solution of 2.0 M n-butullithium in hexane (15.8 mL) was added dropwise. The reaction mixture was stirred at −76° C. for 30 minutes and a solution of o-nitrobenzaldehyde (3.0 g) in anhydrous THF was added. The reaction mixture was stirred at −76° C. for 60 minutes, and quenched with water. The reaction mixture was warmed up to room temperature and THF was removed under vacuum. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated to dryness. The crude material was purified by chromatography on silica gel giving a yield of 4.3 grams (87%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:16])OC2C=CC=CC=2)=[CH:3][CH:2]=1.Cl.[C:18]([N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)(=[O:20])[CH3:19].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:18]([N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:8]([NH:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[O:16])[CH2:23][CH2:22]1)(=[O:20])[CH3:19]
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Reactant: CC(=O)N1CCC(N)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCC(NC(=O)Nc2ccncc2)CC1
Reaction time: 24 h
Yield: 34.6 %

Procedure:
To a solution of O-phenyl N-(4-pyridyl)carbamate (0.81 g) in chloroform (10 ml) were added 1-acetyl-4-aminopiperidine hydrochloride (0.68 g) and triethylamine (1.06 ml) at ambient temperature. After stirring for 1 day, the mixture changed to a solution. The solvents were removed under reduced pressure. A residue was purified by column chromatography (silica gel 100 ml, dichloromethane:methanol=10:1 to 5:1, and silica gel 50 ml, dichloromethane:methanol:aqueous ammonia=10:1:0.1). The solvents of desired fractions were removed under reduced pressure. A residue was dissolved with methanol (5 ml) and dichloromethane (5 ml), and 4N hydrogen chloride in dioxane (1.5 ml) was added to the solution. The solvents were removed under reduced pressure, and the residue was evaporated azeotropically with methanol. After crystallization from diisopropyl ether and n-hexane, N-(1-acetylpiperidin-4-yl)-N′-(4-pyridyl)urea (343 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:3]=1[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=1.C([O-])(=O)C.[Na+].C(O)C.[N:37]#[C:38]Br>ClCCl.C1(C)C=CC=CC=1.[OH-].[Na+]>[Cl:1][C:2]1[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][C:3]=1[CH2:4][N:5]([CH2:6][C:7]1[CH:12]=[C:11]([C:13]([F:15])([F:16])[F:14])[CH:10]=[C:9]([C:17]([F:18])([F:19])[F:20])[CH:8]=1)[C:38]#[N:37]
Reactant: FC(F)(F)c1cc(CNCc2cc(C(F)(F)F)ccc2Cl)cc(C(F)(F)F)c1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: ClCCl
Product: N#CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Yield: 74 %

Procedure:
To the mixture of the compound from Step B (10 gm), 5.6 gm of sodium acetate 100 mL of ethanol was added over 15 minutes 15.5 mL of cyanogen bromide 3M in dichloromethane. The reaction mixture was stirred at ambient temperature until reaction completion. When the reaction was judged complete, it was diluted with 200 mL of toluene and 200 mL of sodium hydroxide. The layers were separated and the organic layer dried with magnesium sulfate, filtered and concentrated to an oil. 7.8 gm (74% yield). The product was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) 7.84 (s, 2H), 7.56 (s, 3H), 7.66 (m, 4H), 7.48 (s, 2H), 4.39 (s, 2H), 4.36 (s, 2H)
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:28](=[O:30])[CH3:29])[CH:22]=2)[CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(F)=C(F)C=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.NC1C=C(NC(=O)C)C=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C>CC(C)CCO>[C:28]([NH:27][C:23]1[CH:22]=[C:21]([N:15]([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:31])=[O:3])=[CH:8][N:9]=2)[CH:26]=[CH:25][CH:24]=1)(=[O:30])[CH3:29]
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CCC(C)C)c2cccc(NC(C)=O)c2)s1
Agent: CC(=O)Nc1cccc(N)c1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: O=C(O)Cc1csc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2)n1
Solvent: CC(C)CCO
Product: CC(=O)Nc1cccc(N(CCC(C)C)C(=O)Nc2ncc(SCC(=O)O)s2)c1

Procedure:
The title compound was prepared via {2-[3-(3-acetylamino-phenyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using N-(3-amino-phenyl)-acetamide, 3-methylbutanol and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=O.[NH2:9]/[C:10](/[CH3:18])=[CH:11]\[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13].[OH-:19].[Na+]>CCO.Cl>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[C:11]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[C:10]([CH3:18])[NH:9][C:10]2[CH2:18][O:19][C:12](=[O:13])[C:11]1=2
Reactant: O=Cc1sccc1Cl
Reactant: [OH-]
Reactant: C/C(N)=C/C(=O)OC(C)C
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC1=C(C(=O)OC(C)C)C(c2sccc2Cl)C2=C(COC2=O)N1
Reaction time: 1 h

Procedure:
40 mmol of 3-chloro-thiophene-2-carbaldehyde, 40 mmol of 3-acetoxyacetoacetic acid ester and 40 mmol of isopropyl 3-aminocrotonate are boiled under reflux over NaOH in EtOH, alcoholic hydrochloric acid is then added and the mixture is boiled for 1 hour. It is concentrated and the residue is crystallized.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[CH:2]1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:20][NH:21][O:22][CH3:23].C(N(CC)CC)C>ClCCl.CN(C=O)C>[CH3:23][O:22][N:21]([CH3:20])[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:12]
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CON(C)C(=O)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
Indole-3-carboxylic acid (2.50 g, 0.0155 mol) was suspended in dichloromethane (60 ml) and treated with oxalyl chloride (1.62 ml, 0.0186 mol), followed by a drop of dry DMF. The reaction mixture was then stirred at room temperature overnight, before being evaporated under reduced pressure and dried in vacuo. The product was then redissolved in dichloromethane (50 ml) and added slowly to a solution of N,O-dimethylhydroxylamine hydrochloride (1.59 g, 0.0163 mol) in dichloromethane (50 ml) containing triethylamine (4.53 ml, 0.0326 mol) under argon. The resultant mixture was then stirred at room temperature for 2 h, before being washed with water, followed by aq. NaHCO3. The organic layer was then dried (Na2SO4), evaporated under reduced pressure and dried in vacuo to yield the title compound as white solid (2.46 g, 78%).
Reaction SMILES: S([O-])(O[CH3:5])(=O)=O.[F:7][C:8]([C:11]1[C:12](=[O:25])[C:13]([OH:24])=[N:14][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]=1[CH3:17])([F:10])[F:9]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.CCOCC>[F:9][C:8]([C:11]1[C:12](=[O:25])[C:13]([O:24][CH3:5])=[N:14][N:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:16]=1[CH3:17])([F:7])[F:10]
Reactant: COS(=O)(=O)[O-]
Reactant: Cc1c(C(F)(F)F)c(=O)c(O)nn1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1nn(-c2ccccc2)c(C)c(C(F)(F)F)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
Tetrabutylammonium bromide (635 mg), 6N soda (13 ml), and methyl sulfate (5.59 ml) are added to a solution of Compound 1 (5.31 grams) in THF. After 1 hour 30 minutes of stirring at 25° C., the solution is evaporated under vacuum, dissolved in water, and extracted with ethyl acetate. After washing with water, drying, filtration and evaporation under vacuum, a residue is obtained which is dissolved in ether and recrystallized from a 60/40 mixture of dioxane and hexane, to provide Compound 2 (3.97 grams; yield 71%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([O-:9])=[O:8].[CH2:17]([O:19][C:20](=[O:29])[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)Br)[CH3:18]>CN(C=O)C>[CH2:17]([O:19][C:20](=[O:29])[CH:21]([O:16][C:13]1[CH:14]=[CH:15][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:18]
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1ccc([N+](=O)[O-])cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of cesium carbonate (2.51 g, 7.70 mmol) in DMF (30 mL) was added 4-nitrophenol(1.07 g, 7.70 mmol). After stirring at room temperature under argon for 30 minutes, ethyl-alpha-bromophenylacetate (1.70 g, 7.00 mmol) was added to the suspension and the resulting mixture was stirred at room temperature overnight. The reaction was then quenched with water and extracted with EtOAc. The organic extracts were washed with water, brine, and dried over Na2SO4. After removing the solvent under reduced pressure, the crude product was used in the next reaction without further purification. 1H NMR (400 MHz, CDC3) δ8.20 (d, 2H) 7.60-7.37 (m, 5H), 7.05 (d, 2H), 5.70 (s, 1H), 4.20 (m, 2H), 1.22 (t, 3H). MH+ 303.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[O:39][CH3:40])[CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([NH:23][CH2:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[O:39][CH3:40])[CH2:29][CH2:28]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Reactant: COc1ccccc1N1CCN(CCCN)CC1
Product: COc1ccccc1N1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(=O)n(C)c3n2)CC1

Procedure:
This compound was prepared by a procedure similar to that described in Example 49 starting with 0.165 g (0.47 mmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 37 and 1.00 g (4.00 mmol) of 1-(3-aminopropyl)-4-(2-methoxyphenyl)piperazine yielding 0.103 g of pure product; mp 187°-188° C.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]1[CH2:11][C:10](=[O:12])[O:9][C:7]1=[O:8])=[O:4].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC(Cl)C.C(OCC)(=O)C>[C:7]([CH:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:11][C:10]([C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1)=[O:12])([OH:9])=[O:8]
Reactant: Clc1ccccc1
Reactant: COC(=O)NC1CC(=O)OC1=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)NC(CC(=O)c1ccc(Cl)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
To 17.58 g of 2-methoxycarbonylaminosuccinic anhydride and 33.77 g of 4-chlorobenzene suspended in 150 ml of dichloroethane was added 33.40 g of anhydrous aluminum chloride under ice cooling, and the mixture was stirred at room temperature for 1 hour. Under ice cooling, to the mixture were added 100 ml of 10% hydrochloric acid and then 500 ml of ethyl acetate. After the organic layer was collected by separation, washed with water and dried, the solvent was removed. The resulting crude crystals were recrystallized from ethyl acetate to obtain 24.2 g of 3-carboxy-3-methoxycarbonylamino-4'-chloropropiophenone.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:12]2[C:7](=CC=[C:10]([CH2:13][N:14]3[CH2:18][CH2:17][C@H:16]([NH:19][S:20]([C:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][C:27]([O:33][CH3:34])=[CH:28][CH:29]=5)[CH:24]=4)(=[O:22])=[O:21])[C:15]3=[O:35])[CH:11]=2)[CH:6]=[CH:5][N:4]=1.C([O:40]C(=O)N[C@H]1CCN(NCC2OC3C=CN=C(N)C=3C=2)C1=O)(C)(C)C>>[ClH:1].[NH2:2][C:3]1[C:12]2[CH:11]=[C:10]([CH2:13][N:14]3[CH2:18][CH2:17][C@H:16]([NH:19][S:20]([C:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][C:27]([O:33][CH3:34])=[CH:28][CH:29]=5)[CH:24]=4)(=[O:22])=[O:21])[C:15]3=[O:35])[O:40][C:7]=2[CH:6]=[CH:5][N:4]=1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccc5ccnc(N)c5c4)C3=O)cc2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(NCc2cc3c(N)nccc3o2)C1=O
Agent: Cl
Product: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cc5c(N)nccc5o4)C3=O)cc2c1

Procedure:
Using the procedure described in example 85j 150 mg of [1-((4-amino-furo[3,2-c]pyridin-2-yl)methylamino)-2-oxopyrrolidin-3-(S)yl]carbamic acid tert-butyl ester was transformed into 110 mg of the title compound. MS ESI+: 467 (M+H).