Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8](=[O:20])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=1.[CH3:21][N:22]=[C:23]=[O:24].O>N1C=CC=CC=1>[CH3:21][NH:22][C:23](=[O:24])[NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8](=[O:20])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=2)[N:6]=1
Reactant: Nc1nc(CC(=O)Nc2cccc(C(F)(F)F)c2)cs1
Reactant: CN=C=O
Solvent: c1ccncc1
Solvent: O
Product: CNC(=O)Nc1nc(CC(=O)Nc2cccc(C(F)(F)F)c2)cs1
Reaction time: 8 h
Yield: 84.6 %

Procedure:
A solution of 10 g (0.033 mole) of 2-amino-4-(3-trifluoromethylphenylcarbamoylmethyl)thiazole, and 2.3 g (0.04 mole) of methyl isocyanate in 50 ml of pyridine was heated at 50° for 3 hours. The reaction solution was mixed with 400 ml of water and allowed to stand overnight in the refrigerator. On the following morning, the crystalline solid was collected and dried in the oven. There was obtained 10 g of the desired product, m.p. 200°14 203°. N.M.R. (dimethyl-d6 sulfoxide) ∂ 2.7-2.8 (CH3, doublet), 6.8 (hetero-aromatic), 7.3-8.1 (aromatic), 10.4 (HNC=O).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][OH:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13](Cl)(=[O:16])[CH2:14][CH3:15]>>[C:13]([O:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])(=[O:16])[CH2:14][CH3:15]
Reactant: O=C(NO)OCc1ccccc1
Reactant: CCC(=O)Cl
Product: CCC(=O)ONC(=O)OCc1ccccc1

Procedure:
[(Benzyloxy)carbonyl]amino propanoate is prepared from N-(benzyloxycarbonyl) hydroxylamine and propionyl chloride according to Scheme 1. (3.6 g, 89%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.18 (1H, s), 7.32-7.43 (5H, m), 5.22 (2H, s), 2.50 (2H, q, 7.6 Hz), 1.22 (3H, t, 7.6 Hz).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[ClH:25]>C(O)C.[Pd]>[ClH:25].[F:24][C:2]([F:1])([F:23])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: N#Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reaction time: 24 h
Yield: 93 %

Procedure:
In a 250 mL flask, 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzonitrile (3.00 g, 9.09 mmol) in ethanol (30 mL) was taken and hydrogen chloride (12 N, 3 mL) was added followed by palladium on carbon (10 wt %, 0.500 g). The reaction mixture was evacuated and purged with hydrogen gas. The reaction mixture was stirred under hydrogen (50 psi) for 24 hours. The reaction mixture was filtered over Celite®, concentrated and the solid obtained triturated with diethyl ether to give the title compound as an off-white solid (2.80 g, 93%): mp 259-263° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.37 (bs, 3H), 8.15 (d, J=8.1 Hz, 2H), 8.08 (d, J=9.3 Hz, 2H), 7.63 (d, J=8.1 Hz, 4H), 4.10 (q, J=6.0 Hz, 2H); ES+ m/z 335 ([M+H]+).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.Cl.O>CO.O>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:16]1[CH2:17][CH2:18][NH:13][CH2:14][CH:15]=1
Reactant: O=C1CCNCC1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Brc1ccc2[nH]cc(C3=CCNCC3)c2c1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
To a solution of 4.29 gm (77 mmol) potassium hydroxide in 50 ml methanol were added 5.0 gm (26 mmol) 5-bromoindole and 7.84 gm (51 mmol) 4piperidone .HCl.H2O and the reaction mixture was stirred for 18 hours at reflux under a nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, diluted with 500 ml water and the mixture extracted well with dichloromethane. The combined organic extracts were washed with water followed by saturated aqueous sodium chloride and dried over sodium sulfate. The remaining organics were concentrated under reduced pressure to give 6.23 gm (86.5%) of the title compound as a yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][C:7]=1[CH3:8].Cl.[C-:16]#[N:17].[Na+]>CS(C)=O>[C:16]([CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][C:7]=1[CH3:8])#[N:17]
Reactant: Cc1[nH]c(-c2ccccc2)nc1CCl
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1[nH]c(-c2ccccc2)nc1CC#N

Procedure:
A solution of 4-chloromethyl-5-methyl-2-phenylimidazole.HCl (40.5 g) in dimethylsulfoxide (400 ml) was added to a stirred solution of sodium cyanide (80 g) in dimethylsulfoxide (600 ml) over a period of 30 min. After 20 h the solids were filtered off, washed with water and dried in vacuo.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH2:8])=[CH:4][CH:3]=1.C([O:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:29]2[C:37]3[C:32](=[CH:33][C:34]([C:38](O)=[O:39])=[CH:35][CH:36]=3)[C:31]([CH3:41])=[C:30]2[CH3:42])=[CH:24][CH:23]=1)=[O:15])(C)(C)C>>[CH3:42][C:30]1[N:29]([CH2:28][C:25]2[CH:26]=[CH:27][C:22]([C:17]3[C:16]([C:14]([OH:15])=[O:13])=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:23][CH:24]=2)[C:37]2[C:32]([C:31]=1[CH3:41])=[CH:33][C:34]([C:38](=[O:39])[NH:8][CH2:7][C:5]1[O:6][C:2]([CH3:1])=[CH:3][CH:4]=1)=[CH:35][CH:36]=2
Reactant: Cc1ccc(CN)o1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1ccc(CNC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(-c3ccccc3C(=O)O)cc2)o1

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 5-methyl-2-furanylmethylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 493 (M+H).
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][C:6]([N+:14]([O-:16])=[O:15])=[C:7]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[CH:8]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[N+:14]([C:6]1[CH:5]=[CH:4][C:3]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:8][C:7]=1[N:9]1[CH:13]=[CH:12][CH:11]=[N:10]1)([O-:16])=[O:15]
Reactant: C1COCCN1
Reactant: COc1ccc([N+](=O)[O-])c(-n2cccn2)c1
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1-n1cccn1
Yield: 8.5 %

Procedure:
Under N2 a solution of 1-(5-Methoxy-2-nitro-phenyl)-1H-pyrazole (3.00 g, 13.7 mmol), of Example 611a, in Morpholine (100 mL, 1000 mmol; Acros) was warmed to 120° C. for 100 h. The reaction mixture was concentrated under reduced pressure and the residue partitioned between 10% Na2CO3 and EtOAc. The aqueous phase was washed with a second portion of EtOAc, then the organics were combined, dried over Na2SO4, filtered and concentrated to yield 1.46 g of crude product 4-(4-Nitro-3-pyrazol-1-yl-phenyl)-morpholine (26% by LC). An initial purification by normal phase chromatography eluting with a gradient of 100% CH2Cl2 to 10:1 CH2Cl2:MeOH met with limited success. The purest fractions were concentrated and rerun on another normal phase column eluting with a gradient of 10% EtOAc/Hexane to 65% EtOAc/Hexane. The purest fractions were combined and concentrated under reduced pressure to give 0.48 g of purer material. This material was crystallized from Et2O and the resulting solid was filtered and rinsed with a small amount of Et2O to yield 318 mg (9%) of 4-(4-Nitro-3-pyrazol-1-yl-phenyl)-morpholine, which was carried on without further purification. 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J=9.25 Hz, 1H), 7.76 (s, 1H), 7.65 (d, J=1.95 Hz, 1H), 6.93 (d, J=2.21 Hz, 1H), 6.86 (m, 1H), 6.50 (s, 1H), 3.87 (m, 4H), 3.40 (m, 4H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH:14]([O:20][C:21](=[O:23])[NH2:22])[CH2:15][C:16]([N:18]=[O:19])=[O:17].C(Cl)(Cl)Cl.C(O)(=O)C>O>[Br:1][C:13]1[S:9][C:10]([CH:14]([O:20][C:21](=[O:23])[NH2:22])[CH2:15][C:16]([N:18]=[O:19])=[O:17])=[CH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: NC(=O)OC(CC(=O)N=O)c1cccs1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)OC(CC(=O)N=O)c1ccc(Br)s1
Reaction time: 24 h
Yield: 75.4 %

Procedure:
N-bromosuccinimide (1.79 g) was added in portions to a solution of (±)-(2-(2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide (2.2 g 9.5 mmol) in 40 ml of a 1:1 mixture of chloroform and acetic acid. The resulting suspension was stirred for 24 hours. The reaction mixture was then diluted with an equal volume of water and the separated organic layer was recovered, and sequentially washed with potassium hydroxide solution and water. The extracts were dried over sodium sulfate, filtered, concentrated and purified by recrystallization from dichloromethane to yield the title compound as a white solid (2.2 g). M.p. 160-161° (from dichloromethane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:5]=2[CH:4]=1.[N+:18]([O-])([OH:20])=[O:19].[OH-].[NH4+]>S(=O)(=O)(O)O.O>[CH3:1][O:2][C:3]1[C:8]([N+:18]([O-:20])=[O:19])=[CH:7][C:6]2[C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:5]=2[CH:4]=1
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1cc2oc(=O)c3c(c2cc1[N+](=O)[O-])CCNC3
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1,2,3,4-Tetrahydro-8-methoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one (1.0 g) is dissolved in a mixture of concentrated sulfuric acid (3 ml) and water (2 ml). The resulting solution is cooled in an ice bath and concentrated nitric acid (1 ml) is added. The reaction mixture is stirred at room temperature for 20 hours. The reaction mixture is poured over ice and made basic with aqueous ammonium hydroxide solution. The product is filtered off and washed with water. Recrystallization from ethanol gave the product (535 mg), mp 200°-205° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:15])C(=O)C(F)(F)F)=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[CH2:39]([O:41][C:42]1[CH:43]=[C:44]([CH:54]=[C:55]([O:58][CH2:59][CH3:60])[C:56]=1I)[CH2:45][C:46]1[C:47]([NH2:53])=[N:48][C:49]([NH2:52])=[N:50][CH:51]=1)[CH3:40].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(COC)OC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C)C=O>[CH2:59]([O:58][C:55]1[CH:54]=[C:44]([CH2:45][C:46]2[C:47]([NH2:53])=[N:48][C:49]([NH2:52])=[N:50][CH:51]=2)[CH:43]=[C:42]([O:41][CH2:39][CH3:40])[C:56]=1[C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH3:15])=[CH:6][CH:7]=1)[CH3:60]
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1I
Reactant: CN(C(=O)C(F)(F)F)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1ccc(NC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
N-(4-Bromophenyl)-2,2,2-trifluoro-N-methyl-acetamide (1.32 g; 5.2 mmol), bis(pinacolato)diboron (1.57 g; 14.1 mmol), potassium acetate (1.38 g; 14.1 mmol) and 1,1′-bis(diphenylphosphino) ferrocene-dichloropalladium(II) (PdCl2(dppf)) (228 mg; 0.29 mmol) are stirred in dimethoxyethane (47 ml; dried over a molecular sieve) at a bath temperature of 80° C. for 17 hours while gassing with argon. After cooling to room temperature, bis(pinacolato)diboron (250 mg; 0.995 mmol) and bis(diphenylphosphino)ferrocene-dichloropalladium(II) (PdCl2(dppf)) (31 mg; 0.039 mmol) are added again and the mixture is stirred again for 1 hour at a bath temperature of 80° C. under argon. After cooling to room temperature, dimethylformarnide (95 ml), tetrakis-triphenylphosphine-palladium (416 mg; 0.36 mmol), 5-(3,5-diethoxy-4-iodo-benzyl)-pyrimidine-2,4-diamine (example 1) (1.56 g; 3.76 mmol) and a 2 M aqueous potassium phosphate solution (18.8 ml) are added. The reaction mixture is stirred for 7 hours at 80° C., cooled to room temperature and concentrated. Water (300 ml) is added to the residue and the product which has precipitated out is filtered off with suction. The tacky filter cake is dissolved in methanol and the solution is evaporated. Azeotropic distillation is carried out twice with methanol and the substance is dried under a high vacuum. The crude product obtained is chromatographed twice over silica gel (125 g) with methylene chloride/methanol/NH4OH conc. 19/110.05. The pure fractions are combined, the solvent is concentrated, the residue is stirred with methanol (10 ml), filtered off with suction and dried under a high vacuum. 570 mg (26%) 5-(2,6-diethoxy-4′-methylamino-biphenyl-4-ylmethyl)-pyrimidine-2,4-diamine are obtained as a light-yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH:5]=[CH:6][CH:7]=[N:8][NH:9][C:10]([NH2:12])=[S:11].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=O>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]2[N:12]=[C:10]([NH:9][N:8]=[CH:7]/[CH:6]=[CH:5]/[C:4]3[CH:3]=[C:2]([OH:1])[CH:15]=[CH:14][CH:13]=3)[S:11][CH:17]=2)=[CH:21][CH:22]=1
Reactant: NC(=S)NN=CC=Cc1cccc(O)c1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Product: Oc1cccc(/C=C/C=NNc2nc(-c3ccc(Cl)cc3)cs2)c1
Yield: 39 %

Procedure:
The compound is prepared according to the method described in example 1B from 3-hydroxycinnamaldehyde thiosemicarbazone (0.5 mmoles) prepared in step 15A and from 2-bromo-4′-chloroacetophenone (0.5 mmoles). Yield 39%.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([C:15]([OH:17])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O>ClCCl.CN(C)C=O>[Cl:21][C:15]([CH:13]1[CH2:14][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12]1)=[O:17]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.6 %

Procedure:
To a solution of 1-(benzyloxycarbonyl)azetidine-3-carboxylic acid (21.25 mmol, 5 g) in dichloromethane (60 ml) under a nitrogen atmosphere were added N,N-dimethylformamide (1.063 mmol, 0.083 ml) and oxalyl chloride (2M solution in dichloromethane, 25.00 mmol, 12.5 ml). After stirring at room temperature for two hours the reaction mixture was concentrated in vacuo to give 5.53 gram of crude benzyl 3-(chlorocarbonyl)azetidine-1-carboxylate.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=2[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]1.Br.Br.[C:23]12[CH2:30][NH:29][CH2:28][C:27]=1[CH2:26][NH:25][CH2:24]2.N12CCCN=C1CCCCC2>C(#N)C>[F:16][C:10]1[CH:9]=[C:8]2[C:13](=[C:12]([F:14])[C:11]=1[N:25]1[CH2:26][C:27]3[CH2:28][NH:29][CH2:30][C:23]=3[CH2:24]1)[N:4]([CH2:3][CH2:2][F:1])[CH:5]=[C:6]([C:18]([OH:20])=[O:19])[C:7]2=[O:17]
Reactant: O=C(O)c1cn(CCF)c2c(F)c(F)c(F)cc2c1=O
Reactant: C1NCC2=C1CNC2
Agent: Br
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(CCF)c2c(F)c(N3CC4=C(CNC4)C3)c(F)cc2c1=O
Reaction time: 8 h
Yield: 76.2 %

Procedure:
1-(2-Fluoroethyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.29 g), 3,7-diazabicyclo [3.3.0]oct-1(5)-ene dihydrobromide (0.33 g) and 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU, 0.46 g) were dissolved in acetonitrile (15 ml) and refluxed for 3 hours. The reaction mixture was kept at room temperature overnight and the precipitate was collected by filtration, washed with acetonitrile and methanol to give the title compound (0.29 g, yield 76%).
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1B(O)O>>[CH:30]1[C:31]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:29]=1[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Reactant: OB(O)c1ccc2ccccc2c1
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(-c3ccc4ccccc4c3)nc2c1
Yield: 46.7 %

Procedure:
The ester product was obtained via a Suzuki coupling reaction using the method previously shown in Example 13, Step 6, with methyl 3-chloro-2-phenylquinoxaline-6-carboxylate (100 mg, 0.34 mmol, 1.00 equiv) and naphthalen-2-yl boronic acid (63 mg, 0.37 mmol, 1.10 equiv). Purification via silica gel column (ethyl acetate/petroleum ether (1:20)) yielded 62 mg (47%) of methyl 3-(naphthalen-2-yl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@:9]1([CH3:44])[CH2:13][C@@H:12]([C:14]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[N:26]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[C:29]([Cl:34])[CH:28]=4)[N:25]=[C:24]([CH3:35])[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])[C@H:11]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=2[F:43])[CH2:10]1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:52][CH2:53][O:54][CH2:55][CH2:56]I>CC(N(C)C)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:34][C:29]1[CH:28]=[C:27]([N:26]2[C:22]([CH:19]3[CH2:18][CH2:17][N:16]([C:14]([C@@H:12]4[CH2:13][C@@:9]([CH3:44])([N:8]5[CH2:56][CH2:55][O:54][CH2:53][CH2:52]5)[CH2:10][C@H:11]4[C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=4[F:43])=[O:15])[CH2:21][CH2:20]3)=[CH:23][C:24]([CH3:35])=[N:25]2)[CH:32]=[CH:31][C:30]=1[F:33]
Reactant: Cc1cc(C2CCN(C(=O)[C@@H]3C[C@@](C)(N)C[C@H]3c3ccc(F)cc3F)CC2)n(-c2ccc(F)c(Cl)c2)n1
Reactant: ICCOCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Product: Cc1cc(C2CCN(C(=O)[C@@H]3C[C@@](C)(N4CCOCC4)C[C@H]3c3ccc(F)cc3F)CC2)n(-c2ccc(F)c(Cl)c2)n1
Temperature: 110 °C

Procedure:
The product from Example 6 (17.2 mg, 0.027 mmol) in DMA (1 mL) was treated with cesium carbonate (63.3 mg, 0.194 mmol) and 2-iodoethyl ether (15.8 mg, 0.049 mmol) at rt. The mixture was heated at 110° C. for 16 h, then cooled to rt and filtered. The filtrate was directly purified by RP-HPLC (15 to 100% acetonitrile/water+0.05% TFA) to afford the title compound. HPLC/MS: 601.4/603.4 (M+1); Rt=2.92 min (LC4).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[C:8]([O:15][CH3:16])(=[O:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11].C[O-].[Na+]>>[CH3:4][CH:3]([CH2:2][C:1]([O:6][CH3:7])=[O:5])[CH:9]([C:8]([O:15][CH3:16])=[O:14])[C:10]([O:12][CH3:13])=[O:11]
Reactant: C/C=C/C(=O)OC
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)CC(C)C(C(=O)OC)C(=O)OC

Procedure:
Scheme 2 illustrates an alternative exemplary method for making a compound of the formula 1.3. Starting from (E)-methyl but-2-enoate, reaction with dimethyl malonate and sodium methoxide gives trimethyl 2-methylpropane-1,1,3-tricarboxylate, which can be resolved, by for example, a lipase, to give compound 1.3.
Reaction SMILES: [CH3:1][CH:2]1[O:18][C:5]2=[C:6]([O:16][CH3:17])[C:7]3[O:12][C:11](=[O:13])[CH:10]=[C:9]([CH3:14])[C:8]=3[CH:15]=[C:4]2[CH2:3]1>C1(OC2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:17][O:16][C:6]1[C:7]2[O:12][C:11](=[O:13])[CH:10]=[C:9]([CH3:14])[C:8]=2[CH:15]=[C:4]2[CH:3]=[C:2]([CH3:1])[O:18][C:5]=12
Reactant: COc1c2c(cc3c(C)cc(=O)oc13)CC(C)O2
Agent: [Pd]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1c2oc(C)cc2cc2c(C)cc(=O)oc12
Reaction time: 8 h

Procedure:
A solution of 10.36 g (0.0422 mol) of 2,5-dimethyl-9-methoxy-2,3-dihydro-7H-furo[3,2-g][-1]benzopyran-7-one in 150 ml of diphenyl ether was treated with 6.0 g of 10% palladium on charcoal. The mixture was heated under reflux for 5.0 hrs, cooled, and filtered over celite. The catalyst was further washed with methanol, and the filtrate was then concentrated to remove the methanol. The residue was diluted with 1.5 l. of pet. ether and stirred overnight. The product was filtered, washed with pet. ether, dried, and passed through a silica column, eluting with ethyl acetate/benzene, 1:4, to yield pure 9-methoxy-2,5-dimethyl-7H-furo[3,2-g][1]benzopyran-7-one, m.p. 154°-155° (ethanol).
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([O:16][CH3:17])[CH:13]=2)[C:8]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[N:35]=[C:34]([C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27]3=[O:42])[CH:21]=2)=[N:7]1)(=O)C.[OH-].[Li+]>CO.O1CCCC1>[OH:4][CH2:5][C@@H:6]1[CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([O:16][CH3:17])[CH:13]=2)[C:8]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[N:35]=[C:34]([C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27]3=[O:42])[CH:21]=2)=[N:7]1
Reactant: COc1cc2c(cc1OC)C(c1ccnc(-n3nc(-c4cccnc4)c4ccccc4c3=O)c1)=N[C@H](COC(C)=O)C2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2c(cc1OC)C(c1ccnc(-n3nc(-c4cccnc4)c4ccccc4c3=O)c1)=N[C@H](CO)C2
Reaction time: 0.25 h
Yield: 62.2 %

Procedure:
(3S)-4-(3-Acetoxymethyl-3,4-dihydro-6,7-dimethoxyisoquinolin-1-yl)-2-[4-(3-pyridyl)phthalazin-1(2H)-on-2-yl]pyridine (400 mg) is suspended in a mixture of methanol (20 ml) and tetrahydrofuran (10 ml), and thereto is added dropwise a 1 M aqueous lithium hydroxide solution (1.43 ml) under ice-cooling. The mixture is stirred for 15 minutes under ice-cooling, and the mixture is reacted at room temperature for three hours. The reaction mixture is concentrated, and the water is added to the residue. The mixture is extracted with methylene chloride, and the extract is washed, dried and concentrated. The reside is purified by silica gel column chromatography (solvent; chloroform:methanol=10:1) to give (3S)-4-(3,4-dihydro-3-hydroxymethyl-6,7-dimethoxyisoquinolin-1-yl)-2-[4-(3-pyridyl)phthalazin-1(2H)-on-2-yl]pyridine (230 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2[N:9]([CH2:13][C:14]3[N:19]=[CH:18][N:17]=[C:16]([NH:20][NH2:21])[C:15]=3[CH2:22][CH2:23][CH3:24])[CH:10]=[CH:11][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:25](OC(OCC)OCC)(=O)C.C([O-])(O)=O.[Na+]>ClCCl>[F:1][C:2]1[C:3]([C:8]2[N:9]([CH2:13][C:14]3[N:19]=[CH:18][N:17]4[CH:25]=[N:21][N:20]=[C:16]4[C:15]=3[CH2:22][CH2:23][CH3:24])[CH:10]=[CH:11][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1c(Cn2ccnc2-c2ncccc2F)ncnc1NN
Reactant: CCOC(OCC)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCc1c(Cn2ccnc2-c2ncccc2F)ncn2cnnc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A suspension of 131 (30 mg, 0.09 mmol) and diethoxymethyl acetate (1 mL) is stirred at room temperature for 10 minutes. NaHCO3 (aq.) (10 mL) and dichloromethane (10 mL) are added. The organic layer is separated and the aqueous layer is extracted with dichloromethane (2×10 mL). The combined organic layers are dried (NaSO4) and solvent removed. The crude product is separated by PTLC (10% methanol in dichloromethane) to yield 187; LC-MS, M+1 338.15; 1H-NMR (CDCl3) δ: 8.87 (s, 1H), 8.83 (s, 1H), 8.42 (s, 1H), 7.54 (t, 1H), 7.23–7.34 (m, 3H), 5.79 (s, 2H), 3.02 (t, 2H), 1.66–1.76 (m, 2H), 0.99 (t, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:35])[NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]3=[O:26])=[CH:19][CH:18]=2)=[N:15][CH:16]=1.N[C:37]1[CH:38]=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=N[CH:42]=1>>[CH2:42]1[C:6]2[C:5](=[CH:4][C:3]([NH:8][C:9](=[O:35])[NH:10][C:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:25]=[C:24]5[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:33])[CH3:34])[C:28]([O:30][CH3:31])=[O:29])[C:23]5=[O:26])=[CH:19][CH:18]=4)=[N:15][CH:16]=3)=[CH:2][CH:7]=2)[CH2:38][CH2:37]1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cn3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Cl)cn3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc5c(c4)CCC5)cn3)cc2C1=O

Procedure:
The compound of example 401 was prepared analogous to the compound of example 393 by reaction of the compound of example 392 with 2,3-dihydro-1H-indene-5-isocyanate. The compound of example 401 was used directly for the preparation of compound 402 without purification.