Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2Br)[N:11]2[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[C:28](=[O:29])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C([O-])([O-])=O.[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O1CCOCC1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[C:37]2[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=2)[N:11]2[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[C:28](=[O:29])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)N1CCn2c(Cc3ccc(Cl)cc3Br)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)N1CCn2c(Cc3ccc(Cl)cc3-c3ccc(Cl)cc3)nc(=O)c(OCc3ccccc3)c2C1=O
Temperature: 80 °C
Yield: 49.4 %

Procedure:
In a sealed tube was placed a stirred solution of 9-benzyloxy-6-(2-bromo-4-chlorobenzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (380) (80 mg, 0.155 mmol) in dioxane (3 mL). 4-Chlorophenyl boronic acid (24.248 mg, 0.155 mmol) and a 1N solution of K2CO3 [(64.279 mg, 0.465 mmol) dissolved in 0.7 mL water] were added at room temperature and the reaction was degassed for 30 min under argon. To the reaction mixture, Pd(triphenyl phosphine)4 (17.916 mg, 0.016 mmol) was added, followed by 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (12.729 mg, 0.031 mmol) and the reaction was further degassed for another 10 min. The reaction mixture was heated at 80° C. for 20 min (reaction was monitored by LC-MS). After completion of the reaction, the mixture was filtered and the filtrate was diluted with water (5 mL). After extraction with ethyl acetate (2×20 mL), the organic part was dried over sodium sulphate and concentrated. The resulting crude product was purified by column chromatography (using amine bound silica gel as stationary phase) to get 9-benzyloxy-6-(5,4′-dichloro-biphenyl-2-ylmethyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (381) (42 mg, 49.39%) as a white solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[C:13]([N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)([O:15][CH2:16][CH3:17])=[O:14].O>C1COCC1>[C:13]([N:18]1[CH2:19][CH2:20][C:21]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)([OH:24])[CH2:22][CH2:23]1)([O:15][CH2:16][CH3:17])=[O:14]
Reactant: Brc1cccnc1
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CCC(O)(c2cccnc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.4 %

Procedure:
To a flask of THF (200 mL) at −78° C. was added n-butyllithium (24.0 mL, 2.5 M), and the resulting mixture was stirred for 10 min. 3-bromopyridine (5.40 mL, 56.0 mmol) was added to this solution and the resulting mixture was stirred for 30 min. A solution of 1-carbethoxy-4-piperidone (7.24 mL, 48.0 mmol) in THF (20 mL) was cannula to the above anion slowly. The reaction mixture was stirred for 2 hours while warmed to room temperature gradually. Water (100 mL) was added and the mixture was concentrated. Extracted with EtOAc (3×100 mL), the organic extract was dried over Na2SO4, filtered and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel with EtOAc and 5% MeOH in EtOAc to give 7.26 g of 1-carbethoxy-4-(3-pyridyl)-4-hydroxyl-piperidine.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].C(#N)C>CN(C)C=O>[CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[N:6]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2NC1=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)C(C)(C)Oc2ccc([N+](=O)[O-])cc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
A mixture of 6.66 g of 3,4-dihydro-2,2-dimethyl-6-nitro-3-oxo-2H-1,4-benzoxazine, 5.51 g of ethyl bromoacetate, 4.5.6 g of potassium carbonate and 20 ml of acetonitrile was refluxed under heating for 2.5 hours. Then, 10 ml of N,N-dimethylformamide was added and the mixture was stirred at 80° C. for 2 hours. To this mixture was added 2-80 g of ethyl bromoacetate. After an hour of stirring at 80° C., 2.28 g of potassium carbonate was added and the mixture was further stirred at 80° C. for 1 hour. The reaction mixture was then concentrated under reduced pressure and the residue was chromatographed on a silica gel column, elution being carried out with hexane-ethyl acetate (10:.1). The crystals from the eluate were recrystallized from ethyl acetate-hexane to give 7.4 g of ethyl (3,4-dihydro-2,2-dimethyl-6-nitro-3-oxo-2H1,4 -benzoxazin-4-yl)acetate. This compound has the following physicochemical properties.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][CH2:21][Cl:22]>CC(C)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:19][CH2:20][CH2:21][Cl:22]
Reactant: Oc1ccc2ccccc2c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCCOc1ccc2ccccc2c1

Procedure:
A mixture of β-naphthol (1 gm, 0.006 mole), anhydrous K2CO3 (10 gm, in excess) and 1-bromo-3-chloropropane (0.7 ml, 0.006 mole) was refluxed in dry acetone (50 ml) for 6 hours. Reaction mixture was filtered and filtrate was concentrated to get oily compound which was crystallized with benzene-hexane to give the colorless crystals of pure desired compound, m.p. 98° C., (yield 1.5 gm, 97%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13]Cl.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K].[I-].[K+]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][N:19]1[C:15](=[O:25])[C:16]2[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:18]1=[O:20]
Reactant: ClCCCc1c[nH]c2ccc(Br)cc12
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCc1c[nH]c2ccc(Br)cc12
Temperature: 105 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
A mixture of 5-bromo-3-(3-chloropropyl)-1H-indole (1.35 g), potassium phthalimide (0.93 g) and potassium iodide (1.3 g) in dry dimethylformamide (20 ml) was warmed with stirring at 105° C. for 3 hours. The mixture was cooled and diluted with water (30 ml). An oil precipitated which crystallised over the next 5 min. The resulting solid was collected and washed thoroughly with water. The product was recrystallised from 2-propanol (50 ml) to afford the title compound as a pale yellow crystalline solid (1.1 g) m.p. 168.5°-170° C.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:14][CH2:15][CH:16]([OH:25])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[O:18]([CH2:17][CH:16]([OH:25])[CH2:15][CH2:14][N:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: OC(CCCl)COc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: OC(CCN1CCN(c2ccccc2)CC1)COc1ccccc1

Procedure:
A mixture of 6.5 g (0.04 mole) of 1-phenylpiperazine, 8.4 g (0.042 mole) of 4-chloro-1-phenoxy-2-butanol and 15.9 g (0.15 mole) of anhydrous sodium carbonate in 200 ml of 1-butanol was heated at reflux 20 hr. The mixture was concentrated under reduced pressure and the residue was partitioned between water and benzene. The benzene layer was washed with water and aqueous saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure to give the title product in the residue which was recrystallized from isopropyl alcohol to give 8.9 g (68%) of white powder, m.p. 93°-94° C.
Reaction SMILES: [CH2:1]([C:8]1([CH2:11][C@H:12]([CH2:16][C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:32][CH:33]([CH2:43][CH3:44])[C@@H:34]([C:36]1[N:40]=[C:39]([CH2:41][CH3:42])[O:38][N:37]=1)[OH:35]>>[CH2:1]([C:8]1([CH2:11][C@H:12]([CH2:16][C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])[C:13]([NH:32][C@H:33]([C:34]([C:36]2[N:40]=[C:39]([CH2:41][CH3:42])[O:38][N:37]=2)=[O:35])[CH2:43][CH3:44])=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)CC1(Cc2ccccc2)CC1
Reactant: CCc1nc([C@@H](O)C(N)CC)no1
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc(C(=O)[C@H](CC)NC(=O)[C@@H](CC(=O)N2CCOCC2)CC2(Cc3ccccc3)CC2)no1

Procedure:
It is similarly prepared according to general procedure given for example 10 above but using (R)-2-(1-Benzyl-cyclopropylmethyl)-4-morpholin-4-yl-4-oxo-butyric acid and (S)-2-Amino-1-(5-ethyl-1,2,4-oxadiazol-3-yl)-butan-1-ol; compound with trifluoro-acetic acid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.[C:41]([C:43]1[CH:44]=[C:45]([S:49](Cl)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1)#[N:42]>O1CCCC1.O>[Cl:3][C:4]1[C:9]([C:10]2[N:14]([S:49]([C:45]3[CH:46]=[CH:47][CH:48]=[C:43]([C:41]#[N:42])[CH:44]=3)(=[O:51])=[O:50])[CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2cccc(C#N)c2)c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) were added dropwise a solution (5 mL) of tert-butyl {[5-(2-chloropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (340 mg) in tetrahydrofuran, 15-crown-5 (330 mg) and 3-cyanobenzenesulfonyl chloride (302 mg) under ice-cooling and the mixture was stirred for 3 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→3:1) to give the title compound as a pale-yellow oil (yield 490 mg, 97%).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH3:7])[CH2:3][C:4]#[CH:5].[C:8]1([C:14](Cl)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CC=CC=1>O>[C:8]1([C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:1][CH:2]([CH2:6][CH3:7])[CH2:3][C:4]#[CH:5])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C#CCC(O)CC
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: C#CCC(CC)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A stirred solution of 9.81 g. (0.10 moles) of 4-hydroxy-1-hexyne and 33.5 g. (0.12 moles) of triphenylmethyl chloride in 100 ml. of dry pyridine is heated at reflux for 2 hours. The cooled mixture is treated with water and extracted with a hexane-ether mixture. The extract is washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. Column chromatography of the residue on Florisil gives an oil, λ max. 3290 (acetylenic hydrogen), 1600, 1030 and 705 cm-1 (triphenylmethoxy group).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[C:17]([F:18])=[CH:16][C:15]([OH:19])=[C:14]([N+:20]([O-:22])=[O:21])[CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>CC(C)=O.O>[Cl:1][C:2]1[C:3]([C:12]2[C:17]([F:18])=[CH:16][C:15]([O:19][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:14]([N+:20]([O-:22])=[O:21])[CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:8])[F:9]
Reactant: Cn1nc(-c2cc([N+](=O)[O-])c(O)cc2F)c(Cl)c1C(F)(F)F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(F)c(-c2nn(C)c(C(F)(F)F)c2Cl)cc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
At 25° C., 6.11 g (0.018 mole) 4-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-fluoro-2-nitrophenol, 2.5 g (0,019 mole) K2CO3, and 2.0 mL (0.019 mole) ethyl bromoacetate were slurried in 100 mL acetone. The reaction mixture was stirred at 40° C. for 4 hours. The mixture was cooled, diluted with 100 mL cold water, and extracted four times with ethyl acetate. The ethyl acetate extracts were washed with brine, dried over anhydrous MgSO4, and stripped in vacuo. The residue was recrystallized from methylcyclohexane to give 7.5 g (99%) of (4-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-fluoro-2-nitrophenoxy)acetic acid, ethyl ester as a light yellow solid, mp 95°-96° C.
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]([OH:6])=O.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.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:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:6])[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: C1CCNCC1
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: CC(NC(=O)c1ccc(C(=O)N2CCCCC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, piperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.45 minutes; C22H22Cl2N4O2 (445.35); mass spectrum: (M−H)−=444/446/448 (chlorine isotope).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([CH2:10][CH3:11])[CH:3]=1.[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.[K].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:16]2[C:12](=[O:22])[C:13]3[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15]2=[O:17])=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: CCc1cc(Br)ccc1CBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(Br)ccc1CN1C(=O)c2ccccc2C1=O
Temperature: 80 °C

Procedure:
To 4-bromo-1-bromomethyl-2-ethyl-benzene (4.0 g, 14.2 mmol) in dimethylformamide (100 mL) at room temperature was added potassium phthalimide (2.9 g, 15.6 mmol), and the solution was heated at 80° C. for 5 h. The solution was cooled to room temperature and poured into water. The aqueous solution was extracted with ethyl acetate. The pooled organics were washed with saturated sodium chloride, dried (Na2SO4), filtered, and concentrated in vacuo to a yellow solid (4.0 g, 82%). 1H NMR (300 MHz, CDCl3): δ ppm 1.27 (t, J=7.54 Hz, 3H) 2.85 (q, J=7.60 Hz, 2H) 4.84 (s, 2H) 7.14-7.18 (m, 1H) 7.24-7.27 (m, 1H) 7.34 (d, J=2.07 Hz, 1H) 7.73 (dd, J=5.46, 3.01 Hz, 2H) 7.86 (dd, J=5.56, 3.11 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11](/[C:14](/[CH3:18])=[CH:15]\C#N)=[CH:10][CH:9]=1.[Mg].CI.S(=O)(=O)(O)O.CC[O:29][CH2:30][CH3:31]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11](/[C:14](/[CH3:18])=[CH:15]/[C:30](=[O:29])[CH3:31])=[CH:12][CH:13]=1
Reactant: C/C(=C/C#N)c1ccc(-c2ccccc2F)cc1
Reactant: CCOCC
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: ClCCl
Solvent: CI
Product: CC(=O)/C=C(\C)c1ccc(-c2ccccc2F)cc1
Temperature: 0 °C

Procedure:
A solution of 23.7 gm (0.1 mol) of 3-(2'-fluoro-4-biphenylyl)-crotononitrile in 500 ml of dry methylene chloride was added dropwise over a period of 75 minutes to a Grignard reagent prepared from 12.2 gm (0.5 mol) of magnesium and 71 gm (0.5 mol) of methyl iodide in 500 ml of anhydrous ether, and the resulting mixture was refluxed for 4.5 hours. Thereafter, the cooled reaction mixture was stirred into a mixture consisting of 2 kg of ice and 100 ml of concentrated sulfuric acid. The organic phase was separated, washed with aqueous 1% sulfuric acid, then with water, then with a saturated aqueous sodium bicarbonate solution and again with water, dried over sodium sulfate, and evaporated in vacuo. The solid residue was recrystallized from cyclohexane, yielding 7.2 gm (28% of theory) of fallow crystalline (E)-4-(2'-fluoro-4-biphenylyl)-3-penten-2-one, m.p. 92°C.
Reaction SMILES: Cl[C:2]1[C:3]2[C@:10]3([CH2:25][C:13]4=[N:14][CH:15]=[C:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:17]=[C:12]4[CH2:11]3)[C:9](=[O:26])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[H][H]>C(OCC)(=O)C.[Pd]>[O:26]=[C:9]1[NH:8][C:4]2[N:5]=[CH:6][N:7]=[CH:2][C:3]=2[C@@:10]21[CH2:25][C:13]1=[N:14][CH:15]=[C:16]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH:17]=[C:12]1[CH2:11]2
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncnc(Cl)c21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncncc21
Reaction time: 16 h

Procedure:
To a solution of tert-butyl (6S)-4′-chloro-6′-oxo-5,6′,7,7′-tetrahydrospiro [cyclopenta[b]pyridine-6,5′-pyrrolo[2,3-d]pyrimidine]-3-carboxylate (200 mg, 0.537 mmol) in dry ethyl acetate (5.37 mL) was added triethylamine (299 μL, 2.15 mmol) and palladium on carbon (571 mg, 10%, 0.537 mmol). The reaction was placed on a Parr apparatus at 50 psi hydrogen gas. After 16 h, the reaction mixture was filtered under a nitrogen atmosphere through Celite®, washing with ethyl acetate. The filtrate was concentrated to give the title compound, along with one equivalent of triethylamine hydrochloride. MS: m/z=339.3 (M+1).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:15]=[C:16]1[O:20][C@H:19]([C:21]([Cl:24])([Cl:23])[Cl:22])[N:18]2[CH2:25][CH2:26][CH2:27][C@@:17]12[CH:28]=O.[F:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][NH2:35].C(O)(=O)C>ClCCCl>[F:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][NH:35][CH2:28][C@@:17]12[CH2:27][CH2:26][CH2:25][N:18]1[C@@H:19]([C:21]([Cl:24])([Cl:23])[Cl:22])[O:20][C:16]2=[O:15]
Reactant: O=C[C@@]12CCCN1[C@@H](C(Cl)(Cl)Cl)OC2=O
Reactant: NCc1cccc(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@]12CNCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium triacetoxyborohydride (544 mg, 2.57 mmol) was added to (3R,7aR)-1-oxo-3-trichloromethyl-dihydro-pyrrolo[1,2-c]oxazole-7a-carbaldehyde (obtained as described in J. Org. Chem. 2006, 71(1), 97-102, 500 mg, 1.835 mmol), 3-fluorobenzylamine (0.251 mL, 2.20 mmol) and acetic acid (0.263 mL, 4.59 mmol) in DCE (4 mL) under an argon atm. The RM was stirred at rt for 3 h, then partitioned between water and DCM, the combined organic dried over Na2SO4 and evaporated to give the title compound as a pale yellow oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[CH:25]=[C:24]([CH:26]([OH:28])[CH3:27])[NH:23][N:22]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[O:29]1[C:33](=[O:34])[CH2:32][CH2:31][C:30]1=[O:35]>CN(C)C1C=CN=CC=1.C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[CH:25]=[C:24]([CH:26]([O:28][C:33](=[O:34])[CH2:32][CH2:31][C:30]([OH:35])=[O:29])[CH3:27])[NH:23][N:22]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CC(O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)n[nH]1
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(OC(=O)CCC(=O)O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)n[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.3 %

Procedure:
N—((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxy-ethyl)-1H-pyrazole-3-carboxamide (1.254 mmol, 0.5 g), dihydrofuran-2,5-dione (1.504 mmol, 0.151 g) and 4-dimethylaminopyridine (0.1254 mmol, 0.015 g) were dissolved in THF (10 ml) and DMF (1 ml). The resulting mixture was stirred at RT for one day after which the temperature was raised to 50° C. for one day. The mixture was stirred at RT over the weekend. During the reaction more dihydrofuran-2,5-dione (50 mg) was added. The solvents were evaporated and the residue was dissolved in EtOAc. The organic phase was washed with 1 M HCl, separated, dried, filtered and evaporated. The crude product was purified by flash chromatography. 352 mg of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): δ 1.22-1.28 (m, 3H), 1.61-1.69 (m, 3H), 2.54-2.79 (m, 4H), 4.29-4.45 (m, 2H), 4.52-4.64 (m, 1H), 5.97-6.06 (m, 1H), 6.58-6.62 (m, 1H), 6.76-6.80 (m, 1H), 7.50-7.53 (m, 1H), 7.62-7.68 (m, 1H), 7.70-7.77 (m, 1H), 7.90-8.04 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:9][C:8]2[CH:10]=[C:11]3[O:16][CH2:15][O:14][C:12]3=[CH:13][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[N:5][NH:4]1.Cl.[CH3:27][C:28]([CH3:30])=O>>[CH3:27][C:28]1([CH3:30])[N:4]2[N:5]=[C:6]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)[C:7]3[CH:13]=[C:12]4[O:14][CH2:15][O:16][C:11]4=[CH:10][C:8]=3[CH2:9][CH:3]2[CH2:2][O:1]1
Reactant: CC(C)=O
Reactant: O=[N+]([O-])c1ccc(C2=NNC(CO)Cc3cc4c(cc32)OCO4)cc1
Agent: Cl
Product: CC1(C)OCC2Cc3cc4c(cc3C(c3ccc([N+](=O)[O-])cc3)=NN21)OCO4
Reaction time: 0.5 h

Procedure:
1.87 g (5.48 mmol) of 8-hydroxymethyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine is dissolved in 25 ml of acetone and mixed with 0.54 ml (6.67 mmol) of 37% HCl. After 30 minutes, the reaction mixture is cooled, and the hydrochloride is filtered off. The dichloromethane suspension of this salt is shaken with 20 ml of 8% NaHCO3 solution until the salt is dissolved. The organic phase is separated, washed with water, dried and concentrated by evaporation. After recrystallization, 1.7 g (81%) of the title compound, melting point 171-173° C., is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[CH:23]=[CH:22][C:21]2[N:20]3[CH2:24][CH2:25][CH2:26][CH:19]3[CH2:18][CH2:17][C:16]=2[C:15]=1[C:27]([O:29][CH3:30])=[O:28]>N1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[CH:23]=[CH:22][C:21]2[N:20]3[CH2:24][CH2:25][CH2:26][CH:19]3[CH2:18][CH2:17][C:16]=2[C:15]=1[C:27]([O:29][CH3:30])=[O:28])(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Reactant: COC(=O)c1c(N)ccc2c1CCC1CCCN21
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1CCC1CCCN21
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
2-Bromo-4-fluorobenzenesulfonyl chloride (0.656 g) was added to a solution of methyl 7-amino-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoline-6-carboxylate (Intermediate 33, 0.575 g) in pyridine (15 mL) and DCM (15 mL) and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water and the organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-25% to give a pale yellow solid which was triturated with a mixture of ether and cyclohexane (1:1) to give methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoline-6-carboxylate (0.966 g)