Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:11]=[O:12])=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:1][C:2]1[CH2:10][CH:6]2[CH2:7][CH2:8][O:9][C:5]2=[CH:4][C:3]=1[CH:11]=[O:12])(=[O:15])[CH3:14]
Reactant: O=Cc1cc2c(cc1O)CCO2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1=C(C=O)C=C2OCCC2C1
Reaction time: 18 h
Yield: 73.6 %

Procedure:
A solution of 5-hydroxy-2,3-dihydrobenzofuran-6-carboxaldehyde (5.0 g, 0.030 mol) in pyridine (10 ml) was cooled to an internal temperature of -5° C. Acetic anhydride (3.2 g, 0.03 mol) was added dropwise. The cooling bath was removed and the mixture was allowed to stir under nitrogen for 18 hours. The reaction was quenched into water (50 ml) at which time the product crystallized and was collected by filtration. The product was dissolved in methylene chloride (100 ml) and was washed with water (25 ml), saturated sodium bicarbonate (25 ml) saturated sodium chloride (25 ml), dried (MgSO4) and concentrated to a dark oil which solidified on standing. The product was ground, washed with ethyl ether and dried to afford 5-acetoxy-3,4-dihydrobenzofuran-6-carboxaldehyde (4.6 g, 74%). m.p. 68°-70° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[O:9][C:8]([C:10](=[O:12])[CH3:11])=[CH:7][CH:6]=1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[NH2:1][CH2:4][C:5]1[O:9][C:8]([C:10](=[O:12])[CH3:11])=[CH:7][CH:6]=1
Reactant: CC(=O)c1ccc(CN=[N+]=[N-])o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc(CN)o1
Temperature: 60 °C

Procedure:
To a solution of the crude azide (500 mg, 3.03 mmol) in THF (15 mL) were added Ph3P (polymer-supported, 3.0 mmol/g, 1.5 eq.) and water (5 mL). The reaction mixture was stirred at 60° C. until reaction completion, cooled down to rt and filtered. Sat. aq. NaHCO3 and EA were then added, the layers separated and the aq. layer extracted with EA (1×). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by FC (9:1 CH2Cl2/MeOH) and the title compound was obtained as an orange oil. LC-MS-conditions 02: tR=0.27 min; [M+AcCN+H]+=181.61.
Reaction SMILES: Br.[NH:2]1[C:6]([C:7]2[C:15](=N)[N:14]3[C:10]([S:11][C:12]4[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=43)=[N:9][CH:8]=2)=[N:5][N:4]=[N:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22].N1C=CC=CC=1>O>[NH:2]1[C:6]([C:7]2[C:15](=[S:22])[N:14]3[C:10]([S:11][C:12]4[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=43)=[N:9][CH:8]=2)=[N:5][N:4]=[N:3]1
Reactant: N=c1c(-c2nnn[nH]2)cnc2sc3ccccc3n12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: Br
Solvent: O
Solvent: c1ccncc1
Product: S=c1c(-c2nnn[nH]2)cnc2sc3ccccc3n12

Procedure:
The product of Example 24, 0.02 mole, and 12.0 g. (0.054 mole) of P2S5 in 125 ml. of pyridine is heated at reflux for 5 hrs. and then poured into 1 l. of ice and water mixture. The product is collected by filtration, the solid dissolved in dilute NaOH, treated with decolorizing carbon, filtered and the filtrate acidified whereupon the purified product precipitated and was collected on a filter.
Reaction SMILES: C(OP(CP(OC(C)C)(=O)OC(C)C)(OC(C)C)=O)(C)C.[C:22]1([P:39]([O:45]C(C)C)(=[O:44])[O:40]C(C)C)([P:29]([O:35]C(C)C)(=[O:34])[O:30]C(C)C)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.BrCCCCCCBr.C(P(OC(C)C)(=O)OC(C)C)(P(OC(C)C)(=O)OC(C)C)CCCCCCC(P(OC(C)C)(=O)OC(C)C)P(OC(C)C)(=O)OC(C)C>C1(C)C=CC=CC=1>[C:22]1([P:39]([OH:45])(=[O:40])[OH:44])([P:29]([OH:34])(=[O:30])[OH:35])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CC(C)OP(=O)(OC(C)C)C1(P(=O)(OC(C)C)OC(C)C)CCCCCC1
Agent: BrCCCCCCBr
Agent: CC(C)OP(=O)(CP(=O)(OC(C)C)OC(C)C)OC(C)C
Agent: CC(C)OP(=O)(OC(C)C)C(CCCCCCC(P(=O)(OC(C)C)OC(C)C)P(=O)(OC(C)C)OC(C)C)P(=O)(OC(C)C)OC(C)C
Solvent: Cc1ccccc1
Product: O=P(O)(O)C1(P(=O)(O)O)CCCCCC1

Procedure:
Using the same procedure as in Example I, tetraisopropyl methane diphosphonic acid was converted to tetraisopropyl cycloheptane-1,1-diphosphonate by reaction with 1,6-dibromohexane at 80° C. for 18 h. 31P NMR (toluene) indicated that the reaction solution contained a mixture of the desired tetraisopropyl cycloheptane-1,1-diphosphonate (25.3 ppm) and octaisopropyl octane-1,1,8,8-tetraphosphonate (22.1 ppm). The compounds were separated by chromatography (1:1 hexane:THF eluent) on silica gel, and the desired ester was hydrolyzed using 6N refluxing hydrochloric acid as in Example I.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[N+:18]([O-:23])([N+]([O-])=O)=[O:19].O>C(O)(=O)C.C(OCC)C.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([N+:18]([O-:23])=[O:19])=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c(-c3ccccc3)coc12
Reactant: O=[N+]([O-])[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12

Procedure:
To a stirred solution of 5.3 g (0.024 mole) of 7 -methoxy-3-phenylbenzofuran in 200 ml of acetic acid is added dropwise 3.3 g (0.036 mole) of dinitrogen tetroxide in 20 ml of acetic acid. After about 90 minutes the mixture is poured into cold water, precipitating a gum which is isolated by filtration and dissolved in diethyl ether. The ether solution is washed with water and saturated sodium chloride solution and dried. Evaporation gives a residue which is dissolved in chloroform and eluted through a silica gel column with chloroform. Early fractions are a yellow solid which is recrystallized from ethanol to give yellow crystals of 7-methoxy-2-nitro-3-phenylbenzofuran, m.p. 160°-161° C.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:37])([CH3:36])[CH:33]([CH3:35])[CH3:34])[NH:9]1)=[O:7])(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:36])([CH3:37])[CH:33]([CH3:34])[CH3:35])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)C(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-butyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 78b (1.1 g, 2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-butyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (1.1 g, 91%).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([C:22]2[N:26]=[C:25]([CH3:27])[O:24][N:23]=2)[CH:8]=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[O:11]COCCOC)([CH3:4])[CH3:3]>[Br-].[Zn+2].[Br-]>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([C:22]2[N:26]=[C:25]([CH3:27])[O:24][N:23]=2)[CH:8]=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: COCCOCOc1c(C(C)(C)C)cc(-c2noc(C)n2)cc1C(C)(C)C
Agent: [Br-]
Agent: [Zn+2]
Product: Cc1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)no1
Yield: 46.6 %

Procedure:
In a manner analogous to Example 59, 2.6 g (0.007 mole) of 3-[3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]phenyl]-5-methyl-1,2,4-oxadiazole is reacted with 7.7 g (0.03 mole) of zinc bromide to give 0.94 g (48%) of 2,6-bis(1,1-dimethylethyl)-4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenol; mp 126°-127° C.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[NH:15][C:16]([C:18]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:20])[CH3:19])=[O:17])=[O:5].[C:36]([O-])(C)(C)C.[K+].CI.C(O)(=O)C>C(O)(C)(C)C>[F:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[N:15]([CH3:36])[C:16]([C:18]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:19])[CH3:20])=[O:17])=[O:5]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CI
Solvent: CC(C)(C)O
Product: CN(C(=O)C(C)(C)NC(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of 500 mg of benzyl [1-[[2-(o-fluorobenzoyl)-4-nitrophenyl]-carbamoyl]-1-methyl-ethyl]carbamate (1.043 mol) and 150 mg of potassium t-butanolate in 20 ml of t-butanol is treated with 0.15 ml of methyl iodide and stirred at room temperature for 2.5 days. The reaction mixture is buffered with glacial acetic acid and concentrated. The residue is partitioned between methylene chloride and 10 percent aqueous sodium bicarbonate solution. After drying the organic phase overnight and concentrating, the residue is chromatographed on a pressure column containing 10 g of silica gel (particle size 0.04-0.06 mm) under 0.2-0.4 atmospheres of nitrogen with methylene chloride/ethyl acetate (20:1) as the elution agent. There is obtained benzyl [1-[[2-(o-fluorobenzoyl)-4-nitrophenyl]-methylcarbamoyl]-1-methyl-ethyl]carbamate of melting point 168°-169° (ether/n-hexane).
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[C:15]2[C:10]3=[C:11]([C:22]4[CH:23]=[C:24]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:25]=[CH:26][C:27]=4[N:9]3[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=3)[CH:12]=[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:14]=2.C1C(=O)N([Br:42])C(=O)C1.O>C(Cl)Cl.C(#N)C>[Br:42][C:5]1[CH:6]=[CH:7][C:8]2[N:9]3[C:27]4[CH:26]=[CH:25][C:24]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:23][C:22]=4[C:11]4[CH:12]=[C:13]([C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=5)[CH:14]=[C:15]([C:2]([CH3:34])([CH3:1])[C:3]=2[CH:4]=1)[C:10]3=4
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)c2ccccc2-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)cc1c32
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CC1(C)c2cc(Br)ccc2-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)cc1c32
Temperature: 25 °C
Reaction time: 4 h

Procedure:
9.6 g (22.2 mmol) of 8,8-dimethyl-3,6-diphenyl-8H-indolo[3,2,1-de]acridine are initially introduced in 150 ml of CH2Cl2. A solution of 3.9 g (22.3 mmol) of NBS in 100 ml of acetonitrile is subsequently added dropwise at −15° C. with exclusion of light, and the mixture is stirred at room temperature for a further 4 h. For work-up, 150 ml of water are added to the mixture, which is then extracted with CH2Cl2. The organic phase is dried over MgSO4, and the solvent is removed in vacuo. The product is washed by stirring with hot hexane and filtered off with suction.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[N+:17]([O-])=O.[NH4+].[Cl-]>[Fe].CCO>[NH2:17][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:2]=1[Cl:1])[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N)c1
Temperature: 90 °C

Procedure:
A mixture of tert-butyl 4-chloro-3-nitrobenzylcarbamate (crude material from step (b)), Fe powder (17.65 g, 316 mmol), NH4Cl (aq, sat, 100 mL) and EtOH (100 mL) was heated at 90° C. for 4 h and allowed to cool. The pH was adjusted to −10 and the mixture was filtered through Celite. The solids were washed with EtOAc and EtOH and the combined filtrates concentrated to remove the organic solvents. The residue was added to ammonia and the mixture was extracted with DCM. The combined extracts were washed with brine, dried over Na2SO4 and concentrated. Crystallization from EtOAc/petroleum ether gave the sub-title compound. Yield: 15.5 g (75% from 4-chloro-3-nitrobenzylamine).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1.[Br:10]N1C(=O)CCC1=O.CCCCCCC.C1(=O)NC(=O)CC1>C(OC(=O)C)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:7]=1)[CH2:8][Br:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)ccc1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Fc1ccc(Cl)cc1CBr
Temperature: 80 °C
Reaction time: 3 h
Yield: 104.8 %

Procedure:
5-Chloro-2-fluoro-toluene (100 g, 692 mmol) was dissolved in ethylacetate (300 ml) at 20° C. To this solution N-bromosuccinimide (147.7 g, 830 mmol) and dibenzoyl peroxide (2 g, 8.25 mmol) was added. The mixture was stirred at 80° C. for 3 hours. Heptane (300 ml) was added and the solution was cool to 0° C. whereupon succinimide precipitates. After filtration and washing with heptane, the residue was washed with water (1500 ml). The filtrate was concentrated in vacuo to dryness, yielding 162 grams of crude 5-chloro-2-fluoro-benzylbromide. Purification of the crude product (141 grams) was done by vacuum distillation at 99° C. and 33 mbar, this 5-chloro-2-fluoro-benzylbromide (99 grams, 75%). Purity according to GC is 87.1% a/a.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][C:26](I)=[CH:27][C:21]=4[S:20](=[O:30])(=[O:29])[N:19]=3)=[C:14]([OH:31])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:32][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37]([S:41]([NH2:44])(=[O:43])=[O:42])[CH:36]=1.N(CC(O)=O)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.[Cu]I>[F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][C:26]([NH:44][S:41]([C:37]5[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=5)(=[O:43])=[O:42])=[CH:27][C:21]=4[S:20](=[O:30])(=[O:29])[N:19]=3)=[C:14]([OH:31])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:32][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=C1C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Reactant: NS(=O)(=O)c1cccnc1
Agent: [Cu]I
Agent: CNCC(=O)O
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: O=C1C(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4cccnc4)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 52.9 %

Procedure:
(1R,2S,7R,8S)-3-(4-Fluoro-benzyl)-6-hydroxy-5-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (prepared as described in Example 19, 100 mg, 0.17 mmol), pyridine-3-sulfonic acid amide (81 mg, 0.51 mmol), sarcosine (N-methyl glycine) (23 mg, 0.26 mmol), copper (I) iodide (33 mg, 0.17 mmol), and potassium phosphate (216 mg, 1.02 mmol) were combined and dissolved in N,N-dimethylformamide (10 mL). The flask was degassed and backfilled with nitrogen (3×). The reaction was stirred at 100° C. for 4 h. The mixture was cooled to 25° C., diluted with ethyl acetate (20 mL), and extracted with saturated aqueous sodium bicarbonate solution (2×20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by flash column chromatography (Teledyne Isco RediSep column; 0 to 8% methanol in dichloromethane) afforded the desired product, pyridine-3-sulfonic acid {3-[(1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-amide (56 mg, 0.09 mmol, 54%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.38-1.58 (6H, m), 2.61 (1H, s), 3.00 (1H, d, J=7.6 Hz), 3.52 (1H, d, J=8.4 Hz), 4.40 (1H, d, J=15.6 Hz), 4.94 (1H, d, J=15.2 Hz), 7.13 (2H, t, J=8.4 Hz), 7.29-7.32 (2H, m), 7.42-7.50 (3H, m), 7.60-7.63 (1H, m), 8.11 (1H, d, J=7.6 Hz), 8.79 (1H, d, J=4.4 Hz), 8.87 (1H, s), 10.94 (1H, s), 13.99 (1H, s). LC-MS (ESI) calcd for C29H26FN5O6S2 623.68, found 624.2 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[N:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:14]2=[CH:13][C:12]=1[C:20]([OH:22])=O.[CH:23]([O:25][CH2:26][CH2:27][O:28][NH2:29])=[CH2:24].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:23]([O:25][CH2:26][CH2:27][O:28][NH:29][C:20]([C:12]1[CH:13]=[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][N:15]2[C:11]=1[NH:10][C:3]1[CH:4]=[CH:5][C:6]([S:8][CH3:9])=[CH:7][C:2]=1[F:1])=[O:22])=[CH2:24]
Reactant: C=COCCON
Reactant: CSc1ccc(Nc2c(C(=O)O)cc3ccncn23)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=COCCONC(=O)c1cc2ccncn2c1Nc1ccc(SC)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
7-(2-Fluoro-4-methylsulfanyl-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid (200 mg, 0.63 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (106 mg, 0.69 mmol), HOBt (94 mg, 0.69 mmol), EDCI hydrochloride (132 mg, 0.69 mmol) and DIPEA (118 μL, 0.69 mmol) were dissolved in DMF (5 mL). The reaction was stirred at room temperature for 16 hours then concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-100% ethylacetate in cyclohexane) to yield the title compound as a brown solid (139 mg, 55%). LCMS (Method B): RT=3.35 min, M+H+=403.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[CH2:22][CH:21]([CH2:23][CH2:24][N:25](OC)[CH3:26])[N:10]3[C:11](=[O:20])[N:12]([CH:17]([CH3:19])[CH3:18])[C:13](=[O:16])[C:14]([OH:15])=[C:9]3[C:8]2=[O:29])=[CH:4][CH:3]=1>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:22][CH:21]([CH2:23][CH2:24][NH:25][CH3:26])[N:10]3[C:11](=[O:20])[N:12]([CH:17]([CH3:19])[CH3:18])[C:13](=[O:16])[C:14]([OH:15])=[C:9]3[C:8]2=[O:29])=[CH:30][CH:31]=1
Reactant: CON(C)CCC1CN(Cc2ccc(F)cc2)C(=O)c2c(O)c(=O)n(C(C)C)c(=O)n21
Solvent: CO
Product: CNCCC1CN(Cc2ccc(F)cc2)C(=O)c2c(O)c(=O)n(C(C)C)c(=O)n21
Reaction time: 24 h

Procedure:
2-(4-Fluorobenzyl)-9-hydroxy-7-isopropyl-4-{2-[methoxy(methyl)amino]ethyl}-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,6,8(7H)-trione (108 mg, 0.20 mmol, from Example 6) was dissolved in degassed MeOH (8 mL). The solution was degassed and purged three times with nitrogen and then treated with 10% palladium on activated carbon (25 mg) and 6 N aqueous HCl solution (10 drops). The mixture was degassed and purged with nitrogen three times more and placed under hydrogen atmosphere for 24 h. The reaction was filtered through Celite, washing with MeOH, and the filtrate was concentrated in vacuo to a dark yellow oil. Purification by reverse phase chromatography [95:5 water (+0.1% TFA)/MeCN (+0.1% TFA) to 5:95 water (+0.1% TFA)/MeCN (+0.1% TFA)] afforded the title compound as a gray foam. 1H NMR (500 MHz, CD3OD) δ 7.45-7.43 (m, 2H), 7.16-7.12 (m, 2H), 5.19 (dt, J=7.0, 14.0 Hz, 1H), 4.94 (d, J=14.5 Hz, 1H), 4.85-4.84 (m, 1H), 4.50 (d, J=14.5 Hz, 1H), 3.84 (dd, J=4.0, 14.0 Hz, 1H), 3.43 (dd, J=1.5, 14.0 Hz, 1H), 2.92-2.78 (m, 2H), 2.64 (s, 3H), 1.96-1.88 (m, 1H), 1.77-1.70 (m, 1H), 1.47 (dd, J=4.5, 6.5 Hz, 6H). HRMS (FT/ES) M+H: calcd for (C20H26FN4O4)+ 405.1933. found 405.1945.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=1[F:25].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:12]2[CH2:11][CH2:10][N:9]([C:3]3[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=3)[CH2:14][CH2:13]2)=[O:21])=[CH:18][C:17]=1[F:25]
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(Br)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)c(F)c3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.4 %

Procedure:
1-(3,5-Dimethylpyridin-2-yl)piperazine (2.87 g) described in Preparation Example 47 was dissolved in N,N-dimethylformamide (38 ml), 4-bromo-3-fluorobenzoic acid (3.29 g), 1-hydroxybenzotriazole 1 hydrate (2.43 g) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (3.45 g) were added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was poured into water under cooling, and extracted with ethyl acetate. The organic layer was washed twice with water, washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (ethyl acetate:hexane). Then, ethyl acetate and hexane were added and the mixture was stirred at room temperature. The solid was collected by filtration and dried under reduced pressure to give the title compound (3.97 g).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].CN(C)[CH:8]=[CH:9][C:10]([C:12]1[CH:21]=[CH:20][C:19]2[NH:18][C:17](=[O:22])[C:16]3[NH:23][CH:24]=[CH:25][C:15]=3[C:14]=2[CH:13]=1)=O.[CH2:27]([C:29]([O-:31])=[O:30])[CH3:28]>CC(N(C)C)=O>[NH2:4][C:3]1[N:5]=[C:10]([C:12]2[CH:21]=[CH:20][C:19]3[NH:18][C:17](=[O:22])[C:16]4[NH:23][CH:24]=[CH:25][C:15]=4[C:14]=3[CH:13]=2)[CH:9]=[CH:8][N:2]=1.[CH2:27]([C:29]([O-:31])=[O:30])[CH3:28]
Reactant: CN(C)C=CC(=O)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Reactant: N=C(N)N
Agent: CCC(=O)[O-]
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Nc1nccc(-c2ccc3[nH]c(=O)c4[nH]ccc4c3c2)n1
Temperature: 130 °C
Reaction time: 96 h
Yield: 56.1 %

Procedure:
83 mg (0.87 mmol) of guanidine hydrochloride is added to a suspension of 204 mg (0.58 mmol) of 8-(3-dimethylamino-acryloyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 2.3 mL of anhydrous dimethylacetamide. The mixture is stirred at 130° C. for 4 days then the solvent is evaporated. The residue is triturated with methanol to give a solid which is collected by filtration then washed with methanol and then diisopropyl ether. After drying, 114 mg (56%) of 8-(2-amino-pyrimidin-4-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a brown solid.
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:17])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH3:16].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][C:20]=1[C:29]#[N:30]>C1COCC1.C1COCC1.CN(C=O)C>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[C:7]([CH2:6][C:5]([OH:4])=[O:17])=[C:8]2[CH3:16])(=[O:26])=[O:27])=[CH:21][C:20]=1[C:29]#[N:30]
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)c2cccnc2n1S(=O)(=O)c1ccc(Cl)c(C#N)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirred, ice-cooled (0° C.) suspension of sodium hydride (15.8 mg of a 60% dispersion in mineral oil, 0.411 mmol) in dry THF (2 ml) under an inert atmosphere of Argon is added dropwise (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((0.06 g, 0.294 mmol) in THF/DMF (4 ml of a 3:1 mixture). The reaction mixture is stirred at 0° C. for 45 minutes and then treated with 4-chloro-3-cyano-benzenesulfonyl chloride (97.1 mg, 0.411 mmol) in dry THF (3 ml). Stirring continued at 0° C. for 15 minutes and then the reaction mixture is poured onto water (30 ml) and extracted with ethyl acetate (100 ml). The organic portion is separated and washed brine (50 ml), dried (MgSO4) and concentrated in vacuo. The resulting crude is purified by chromatography on silica eluting with iso-hexane/ethyl acetate (0%-20% ethyl acetate) to yield the titled product. (MH+ 404)