Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31])[C:19](=O)[CH2:20][CH3:21].O1CCOCC1.C([O-])(=O)C.[Na+]>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31])=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: COC(=O)COc1ccc(F)c(N)c1
Reactant: CCC(=O)C(Cc1ccc(F)cc1F)C(=O)OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(F)cc1F
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (0.5 g), 2-(2,4-difluorobenzyl)-3-oxopentanoic acid methyl ester (0.64 g), polyphosphoric acid (2.5 mL) and dioxane (10 mL) was heated at 130° C. for 17 hours. The mixture was diluted with water and the pH adjusted to 4 by the addition of sodium acetate. The resulting precipitate was collected by filtration, washed with water and dried to give title compound as a creamy solid, 0.84 g.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=O)[CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH3:11][C:12]1([CH3:20])[CH2:17][C:16](=[O:18])[CH2:15][C:14](=O)[CH2:13]1.C([O-])(=O)C.[Na+]>O>[CH3:11][C:12]1([CH3:20])[CH2:13][C:14]2[NH:2][CH:3]=[C:4]([CH2:5][CH2:6][C:7]([OH:9])=[O:8])[C:15]=2[C:16](=[O:18])[CH2:17]1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: NCC(=O)CCC(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1(C)CC(=O)c2c(CCC(=O)O)c[nH]c2C1
Temperature: 110 °C
Yield: 68 %

Procedure:
A mixture of 5-aminolevulinic acid hydrochloride (1.68 g, 10 mmol), 5,5-dimethyl-1,3-cyclohexandione (1.4 g, 10 mmol) and sodium acetate (1.64 g, 20 mmol) in water (10 mL) was heated to at 110° C. for 4 hours and then cooled. The resulting solid was collected by vacuum filtration, washed with 30% ethanol in water and dried under vacuum to give 1.6 g (68% yield) of 3-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid. 1H-NMR (360 MHz, dimethylsulfoxide-d6) δ 11.89 (br s, 1H, COOH), 10.94 (br s, 1H, NH), 6.45 (d, 1H), 2.76 (t, 2H, CH2), 2.57 (s, 2H, CH2), 2.44 (t, 2H, CH2), 2.16 (s, 2H, CH2), 0.99 (s, 6H, 2×CH3). MS m/z 235 [M+].
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:15][C:16]1[CH:34]=[CH:33][C:19]([CH2:20][NH:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:30][CH2:31][CH3:32])[CH2:27][CH2:28][CH3:29])=[CH:18][CH:17]=1)[CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH2:35]([N:37](CC)CC)C.C(Br)#N.C(=O)([O-])O.[Na+]>C1COCC1>[CH2:30]([N:26]([CH2:27][CH2:28][CH3:29])[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:20][C:19]1[CH:33]=[CH:34][C:16]([CH2:15][N:7]([CH2:6][C:2]2[NH:3][CH:4]=[CH:5][N:1]=2)[CH2:8][C:9]2[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=2)=[CH:17][CH:18]=1)[C:35]#[N:37])[CH2:31][CH3:32]
Reactant: CCN(CC)CC
Reactant: CCCN(CCC)CCCCNCc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Agent: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCN(CCC)CCCCN(C#N)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound (13.4 mg) obtained in Example 52-3 was dissolved in THF (0.26 ml) and added with triethylamine (10 μl) and bromocyan (3.65 mg) and the whole was stirred at room temperature for 2 hours under a nitrogen atmosphere. After completion of the reaction, the solution was added with a saturated aqueous sodium hydrogen carbonate solution to neutralize the solution and the solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with tartaric acid, thereby obtaining a tartrate (12.5 mg) of the subject compound as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.[Br:5][C:6]1[CH:7]=[C:8]([OH:17])[CH:9]=[C:10]2[C:15]=1[O:14][C:13](=[O:16])[CH:12]=[CH:11]2.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CCOC(C)=O>[Br:5][C:6]1[CH:7]=[C:8]([O:17][CH2:1][O:2][CH3:3])[CH:9]=[C:10]2[C:15]=1[O:14][C:13](=[O:16])[CH:12]=[CH:11]2
Reactant: COCCl
Reactant: O=c1ccc2cc(O)cc(Br)c2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCOc1cc(Br)c2oc(=O)ccc2c1
Reaction time: 8 h

Procedure:
Add BBr3 (0.75 mL, 8 mmol) to preparation 3(662 mg, 2.0 mmol) in 20 mL of dichloromethane at 0° C. Let stir for 15 min. Add 8 mL of methanol and then concentrate. Adsorb to 6 g of silica gel and purify by flash chromatography (40 g, 10-50% A/B, A=10% MeOH in EtOAc, B=hexanes) to give 476 mg of 8-Bromo-6-hydroxy-chromen-2-one (3). Add chloromethyl methyl ether (0.18 mL) to a solution of 8-bromo-6-hydroxy-chromen-2-one (476 mg, 1.97 mmol) and K2CO3 (660 mg, 4.77 mmol) in 10 of DMF. Let the solution stir overnight, add 0.09 mL more chloromethyl methyl ether, let stir 2 hrs, dilute with EtOAc, wash with water, 1:1 water:brine, brine, dry (Na2SO4), filter and concentrate to yield 524 mg (1.84 mmol, 93%) of preparation 5. 1H NMR (400 MHz, CDCl3) δ 7.63 (d, 1H, J=9.2 Hz), 7.50 (d, 1H, J=2.6 Hz), 7.12 (d, 1H, J=2.6 Hz), 6.46 (d, 1H, J=9.7 Hz), 5.20 (s, 2H), 3.50 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=O.[OH:13][C:14]([CH2:17][OH:18])=[CH:15][NH2:16]>C1C=CC=CC=1>[OH:13][CH:14]([CH2:17][OH:18])[CH2:15][N:16]=[C:1]=[C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH2:4]1
Reactant: NC=C(O)CO
Reactant: O=Cc1ccc(-c2cccs2)s1
Solvent: c1ccccc1
Product: OCC(O)CN=C=C1CC=C(c2cccs2)S1
Temperature: 85 °C

Procedure:
5.74 g of 5-formyl-2,2'-bithiophene was dissolved in 60 ml of benzene, followed by dropping in excess 2,3-dihydroxy-propenylamine and refluxed at 85° C. for 5 hours with molecular sieves. Then the benzene was evaporated under reduced pressure and 9.68 g of residual solid was obtained. A yellowish product (85%) could be further recrystallized from ethanol.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[CH2:6]([OH:10])[CH2:7][CH2:8][CH3:9]>>[CH2:6]([O:4][CH:1]([OH:5])[C:2]([O:10][CH2:6][CH2:7][CH2:8][CH3:9])=[O:3])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCO
Reactant: O=CC(=O)O
Product: CCCCOC(=O)C(O)OCCCC
Yield: 2 %

Procedure:
Aqueous glyoxylic acid (50%) in the amount of 1,980 parts (13.3 moles) and butanol in the amount of 1,210 parts (16.4 moles) are heated at 55°-60° C. and stripped under vacuum. Butanol in the amount of 1,210 parts (16.4 moles) is added and the reaction is heated at 80°-85° C. under reflux at reduced pressure for two hours. Volatiles are removed at 55°-60° C. under vacuum. Butanol in the amount of 807 parts (10.9 moles) is added and the reaction mixture is refluxed at 80°-85° C. under reduced pressure for six hours. Volatiles are again removed at 55°-60° C. under vacuum to yield 2,850 parts of butyl glyoxylate butyl hemiacetal containing about 2% butyl glyoxylate dibutyl acetal. To the crude hemiacetal (765 parts 3.0 moles) are added monomethyl ether of hydroquinone (0.65 parts and acrylamide (213 parts 3.0 moles). The reaction mixture is heated at 70°-75° C. for three hours. Three intermediate strippings under vacuum removes byproduct butanol (164 parts 2.2 moles). Methanol (870 parts, 25.5 moles) containing sulfuric acid (5.5 parts, 0.056 mole) is added. The reaction mixture is refluxed for 30 minutes and then wet methanol and butane were allowed to distill while fresh methanol (475 parts, 14.0 moles) is added in proportions approximately equal to the amount removed. The reaction mixture is then heated under reflux for an additional two hours. Treatment as described in Example 1 and neutralization of sulfuric acid catalyst with lithium oxide yielded 741 parts of orange colored liquid. Analysis of proton magnetic resonance shows the product contains approximately 90-95% methyl ether and methyl ester groups.
Reaction SMILES: C[Si](Cl)(C)C.[Na+].[I-].C[O:9][C:10]1[C:11](=[O:37])[C:12]([C:26]2[N:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:29]=[CH:28][CH:27]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH:15]=1.O>CC#N>[OH:9][C:10]1[C:11](=[O:37])[C:12]([C:26]2[N:30]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:29]=[CH:28][CH:27]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:25])[F:24])[CH:17]=2)[CH:15]=1
Reactant: COc1cn(-c2cccc(C(F)(F)F)c2)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=c1c(O)cn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
TMSCl (3.17 mL, 25 mmol) was added at room temperature to a solution of NaI (3.75 g, 25 mmol) in CH3CN (150 mL). After stirring for 30 min, 5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (2.06 g, 5 mmol) was added to the resulting suspension. The mixture was stirred for 30 min at room temperature and then refluxed for 1 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was washed with hexane/AcOEt (1/1) and recrystallized from MeOH/H2O to give the title compound (1.68 g, 84% yield) as a colorless powder: mp 246-248° C.; 1H NMR (300 MHz, DMSO-d6): δ ppm 7.17 (1H, d, J=1.9 Hz), 7.33-7.46 (5H, m), 7.53-7.64 (3H, m), 7.71 (1H, d, J=7.5 Hz), 7.83 (1H, d, J=1.9 Hz), 8.83 (1H, s). Anal. Calcd for C20H13F3N4O2: C, 60.30; H, 3.29; N, 14.07. Found: C, 60.09; H, 3.33; N, 14.02.
Reaction SMILES: Cl[C:2]1[N:3]([CH3:16])[C:4]2[C:9]([C:10]=1[CH:11]=O)=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=2.C([O-])([O-])=O.[K+].[K+].[SH:23][CH2:24][C:25]([O:27][CH3:28])=[O:26].O>CO>[CH3:16][N:3]1[C:4]2[C:9](=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=2)[C:10]2[CH:11]=[C:24]([C:25]([O:27][CH3:28])=[O:26])[S:23][C:2]1=2
Reactant: Cn1c(Cl)c(C=O)c2cc([N+](=O)[O-])ccc21
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc2c3cc([N+](=O)[O-])ccc3n(C)c2s1
Reaction time: 8 h

Procedure:
1.4 g of (66) was added to a slurry of excess K2CO3 in 100 ml of MeOH. 2 ml of methyl 2-mercaptoacetate was added and the mixture left with stirring overnight. Addition of water precipitated the product, which was washed with MeOH and water to give 640 mg of (67). M.p. 269°-71° C.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1>>[C:13]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: COc1ccc(Br)cc1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Product: COc1ccc(C(=O)c2cn(-c3cccc(-c4ccccc4)c3)cn2)cc1

Procedure:
This compound was prepared by method C using compound 12a and 4-bromoanisole. HRMS (ESI+): m/z=355.1456 [M+H]
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1.[CH3:34][NH:35][C:36](Cl)=[O:37].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:34][NH:35][C:36](=[O:37])[O:9][CH2:8][C:6]1[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:4]=2[CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(CO)c12
Reactant: CNC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)OCc1nc(Cl)cc2c1c(OC)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 35 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
A solution of (6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methanol (Intermediate 35B, 200 mg, 0.439 mmol) and methylaminoformyl chloride (45.1 mg, 0.483 mmol) in DCM (1462 μl) was treated with DIEA (153 μl, 0.877 mmol) and stirred @ 35° C. for 1 h Reaction was dilluted in with DCM and concentrated in vacuo on silica. Material was purified by normal phase column chromotography eluting with Hex/EtOAc (0-40%) affording (6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methyl methylcarbamate (172 mg, 0.335 mmol, 76% yield) as a white solid. MS: [M+H]+ m/z 513.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:32]=[CH:31][C:24]([C:25]([O:27]CC=C)=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.N1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:32]=[CH:31][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: C=CCOC(=O)c1ccc(-c2ccc3cc(OCCCCCC(=O)OCC)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCOc1cc2ccc(-c3ccc(C(=O)O)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.5 g (2.58 mmol) of allyl 4-[7-(1-adamantyl)-6-ethoxycarbonylpentyloxy-2-naphthyl]benzoate, 50 ml of THF and 90 mg (0.08 mmol) of tetrakis(triphenylphosphine)palladium(0) were introduced into a three-necked flask under a stream of nitrogen. 1.13 ml (13 mmol) of morpholine were added dropwise and the reaction mixture was stirred at room temperature for two hours. The reaction mixture was evaporated to dryness, the residue was taken up in water, acidified to pH 1 with hydrochloric acid and extracted with ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated. The solid was triturated in heptane, filtered and dried. 1 g (72%) of the expected acid was collected, which acid had a melting point of 270°-1° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[NH2:19][CH2:20][CH2:21][NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:19][CH2:20][CH2:21][NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: NCCNS(=O)(=O)c1ccc(Cl)cc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(NCCNS(=O)(=O)c2ccc(Cl)cc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, N-(2-aminoethyl)-p-chlorobenzenesulfonamide hydrochloride and DBU in DME. ES-MS m/e (%): 419 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])=[CH:4][CH:3]=1.[H][H]>O1CCOCC1.O.[Pt]=O>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([N:17]2[C:11]3[N:10]=[C:9]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=4[Cl:34])[N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:13](=[O:14])[C:12]=3[CH:15]=[N:16]2)=[CH:19][CH:20]=1
Reactant: O=c1c2cnn(-c3ccc([N+](=O)[O-])cc3)c2nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(Cl)cc4Cl)nc32)cc1
Reaction time: 1 h

Procedure:
5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-(4-nitro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (100 mg, 0.195 mmol) is dissolved in 20 mL of dioxane. Platinumoxide (11.0 mg, 0.0484 mmol) was added as a slurry in 2 mL of water to the reaction mixture under a nitrogen atmosphere. The mixture was placed under balloon pressure of hydrogen and the reaction is completed within 1 h. The solids are filtered off and the solution is concentrated. Purification by reverse phase HPLC affords the title compound. 1H NMR (DMSO, 400 MHz) δ 8.78 (s, 1H), 8.15 (d, 2H), 7.97-7.95 (m, 2H), 7.90 (m, 3H), 7.84 (dd, 1H), 7.78 (m, 1H), 7.30 (d, 2H), 6.00 (s, 2H). HPLC-MS calculated for C23H14Cl3N5O (M+H+) 482.0. Found: 482.0.
Reaction SMILES: [OH:1][C@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][N:8]([C:10]3[N:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]=3)[CH2:9][C@@H:4]2[CH2:3]1.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.[H-].[Na+]>CN(C=O)C.O>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:1][C@H:2]2[CH2:17][N:5]3[CH2:6][CH2:7][N:8]([C:10]4[N:11]=[CH:12][C:13]([F:16])=[CH:14][N:15]=4)[CH2:9][C@@H:4]3[CH2:3]2)=[CH:21][CH:20]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O[C@@H]1C[C@H]2CN(c3ncc(F)cn3)CCN2C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(CO[C@@H]2C[C@H]3CN(c4ncc(F)cn4)CCN3C2)cc1
Temperature: 100 °C
Yield: 8.2 %

Procedure:
A solution of 0.75 g (3.15 mmol) of (7R,8aS)-7-hydroxy-2-(5-fluoropyrimidin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 6) and 0.79 mL (6.3 mmol) of 4-fluorobenzyl bromide in 30 mL of dry DMF was treated with 0.15 g (3.8 mmol) of sodium hydride (60% oil dispersion), and the mixture was heated at 100° C. for 18 hours. The mixture was cool, diluted with water, and extracted with diethyl ether (5×). The combined organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatograph with 50:50 ethyl acetate:hexane gave 0.090 g (8%) of the title compound. Mp (.HCl) 74-79° C. 13C NMR (base, CDCl3): δ 35.6, 43.9, 48.9, 51.2, 60.4, 60.7, 70.7, 76.7, 115.1, 115.4, 129.35, 129.46, 133.9, 144.9, 145.2, 149.9, 153.2, 158.9, 164.0. HRMS calc'd for C18H20F2N4O (MH+): 347.1683, found: 347.1671.
Reaction SMILES: Cl.N[C:3]1[C:4]2[C:5](=[N:15][N:16]([CH3:18])[CH:17]=2)[NH:6][C:7]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:8]=2[N:9]=1.C(=O)([O-])[O-:20].[K+].[K+]>C(O)C.O>[Cl:14][C:11]1[CH:12]=[CH:13][C:7]2[NH:6][C:5]3=[N:15][N:16]([CH3:18])[CH:17]=[C:4]3[C:3](=[O:20])[NH:9][C:8]=2[CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1cc2c(n1)Nc1ccc(Cl)cc1N=C2N
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cn1cc2c(n1)Nc1ccc(Cl)cc1NC2=O

Procedure:
4-Amino-7-chloro-2,10-dihydro-2-methylpyrazolo[3,4-b][1,5]benzodiazepine hydrochloride (11.3 g) and potassium carbonate (16.8 g) were heated under reflux in a mixture of ethanol (200 ml) and water (20 ml) for 48 hours. Water (300 ml) was added and the solution cooled. The precipitate was crystallised from acetic acid to give the title compound m.p.>260° C.
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[N:10]=[C:11]([O:21][CH2:22][CH3:23])[C:12]([C:16]([O:18]CC)=O)=[N:13][C:14]=1[Cl:15].[CH2:24]([N:26]([CH2:30][CH3:31])[CH2:27][CH2:28][NH2:29])[CH3:25]>CCCCCC>[CH2:24]([N:26]([CH2:30][CH3:31])[CH2:27][CH2:28][NH:29][C:16]([C:12]1[C:11]([O:21][CH2:22][CH3:23])=[N:10][C:9]([NH2:8])=[C:14]([Cl:15])[N:13]=1)=[O:18])[CH3:25]
Reactant: CCOC(=O)c1nc(Cl)c(N)nc1OCC
Reactant: CCN(CC)CCN
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCOc1nc(N)c(Cl)nc1C(=O)NCCN(CC)CC
Temperature: 25 °C

Procedure:
To 8 ml. of toluene were added 0.8 g. of ethyl 5-amino-6-chloro-3-ethoxypyrazine-2-carboxylate and 0.8 g. of N,N-diethylethylenediamine and the mixture was refluxed for 20 hours. After the reaction was over, the reaction mixture was cooled to room temperature and then extracted with 20 ml. of a 1 N aqueous hydrochloric acid solution. The extract was neutralized with dilute aqueous ammonia under ice-cooling and then extracted three times each time with 30 ml. of chloroform. The extracts were combined, washed with water dried, and then the solvent was distilled off under reduced pressure. By washing the residue obtained with 30 ml. of n-hexane, 0.53 g. of colorless crystals of N-(2-diethylaminoethyl)-5-amino-6-chloro-3-ethoxypyrazine-2-carboxamide was obtained. The colorless acicular crystals obtained by recrystallizing the product from a mixture of benzene and n-hexane melted at 147°-148° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]([OH:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCC(O)C(NCC2C=CC=CC=2)C1)=O)(C)(C)C.C(N(CC)CC)C.[Cl:52][CH2:53][C:54](Cl)=[O:55]>C(Cl)Cl>[CH2:15]([N:14]([C:54](=[O:55])[CH2:53][Cl:52])[CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH:10]1[OH:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)C(O)C1
Agent: CC(C)(C)OC(=O)N1CCC(O)C(NCc2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N(Cc2ccccc2)C(=O)CCl)C(O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl-4-(benzylamino)-3-hydroxypiperidine-1-carboxylate and tert-butyl-3-(benzylamino)-4-hydroxypiperidine-1-carboxylate (153 g, 0.42 mol, crude) and triethylamine (126 g, 1.25 mol) in DCM (800 mL) was added drop wise chloroacetyl chloride (33 g, 0.45 mol) at room temperature. The mixture was stirred at room temperature overnight. The mixture was quenched with water (300 mL) at 0° C., and extracted with DCM (500 mL×3). The organic layer was washed with brine (1 L), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to afford tert-butyl 4-[benzyl(chloroacetyl)amino]-3-hydroxypiperidine-1-carboxylate as a mixture of trans diastereomers which was used directly in the next step.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[CH2:12][N:13]([CH3:30])[C:14](=[O:29])[N:15]([CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)[C:5]=3[C:4]=2[N:3]=1.[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[CH2:12][N:13]([CH3:30])[C:14](=[O:29])[N:15]([CH:16]5[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]5)[C:5]=4[C:4]=3[N:3]=2)=[CH:35][CH:34]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: CN1Cc2cnc3ccc(Cl)nc3c2N(C2CCN(C(=O)OC(C)(C)C)CC2)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc3ncc4c(c3n2)N(C2CCN(C(=O)OC(C)(C)C)CC2)C(=O)N(C)C4)cn1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
tert-butyl 4-(9-chloro-3-methyl-2-oxo-3,4-dihydropyrimido[5,4-c][1,5]naphthyridin-1(2H)-yl)piperidine-1-carboxylate (0.104 g, 0.241 mmol) and 6-methoxy-3-pyridine boronic acid (40.7 mg, 0.266 mmol) were dissolved in toluene (6 mL) and ethanol (2 mL), and to the system added tetrakis(triphenylphosphine)palladium (5 mg) and 2N sodium carbonate solution (0.36 mL), reacted under reflux under nitrogen for 16 h, cooled to room temperature, filtered and the organic layer was concentrated under reduced pressure and dissolved in 30 mL of dichloromethane, followed by washing sequentially with water and saturated brine, dried over anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography (ethyl acetate:petroleum ether=2:1) to give 75 mg of the product.