Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)=[N+]=[N-].C(OCC)(=O)C>CO.CCCCCC.[Pd]>[NH2:1][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])CC1
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N)CC1
Yield: 97.6 %

Procedure:
A solution of 4.05 g (17.9 mmol) of 4-azido-1-(tert-butoxycarbonyl)piperidine from Step A in 50 mL of methanol was hydrogenated with 350 mg of 10% Pd/C under a hydrogen balloon for 16 h when the reaction was complete by TLC (10% ethyl acetate in hexane). The catalyst was filtered off and the volatiles removed in vacuo to give 3.5 g of title compound which was used directly in subsequent reactions.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[CH:11]=[C:4]2[N:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: Clc1cccc(-c2cc3nc(Cl)cc(Cl)n3n2)c1
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: Clc1cccc(-c2cc3nc(Cl)cc(N4CCOCC4)n3n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
There was dissolved, in 1,4-dioxane (5 mL), 5,7-dichloro-2-(3-chlorophenyl)-pyrazolo[1,5-a]pyrimidine (200 mg, 0.670 mM), then morpholine (117 μL, 1.34 mM) was added to the solution and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off from the reaction mixture, the resulting residue was diluted with water and then extracted with methylene chloride. The extracts thus obtained were combined together and dried over anhydrous sodium sulfate, then the solvent was distilled off and the resulting solid was washed with methanol to give the title compound (222 mg, yield: 94%).
Reaction SMILES: C([O:4][C:5]1[C:6]([O:23][CH3:24])=[CH:7][C:8]2[N:9]([CH3:22])[C:10]3[C:15]([S:16][C:17]=2[C:18]=1[Br:19])=[CH:14][C:13]([O:20][CH3:21])=[CH:12][CH:11]=3)(=O)C.[OH-].[Na+].Cl>CO>[Br:19][C:18]1[C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:20][CH3:21])[CH:14]=3)[N:9]([CH3:22])[C:8]=2[CH:7]=[C:6]([O:23][CH3:24])[C:5]=1[OH:4]
Reactant: COc1ccc2c(c1)Sc1c(cc(OC)c(OC(C)=O)c1Br)N2C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(c1)Sc1c(cc(OC)c(O)c1Br)N2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To a suspension of 3-acetoxy-4-bromo-2,7-dimethoxy-10-methyl-10H-phenothiazine (0.5 g) in methanol (300 ml) there was added 2N aqueous sodium hydroxide (300 ml) and the mixture was stirred at room temperature overnight. The heterogenous mixture was then acidified with 1N aqueous HCl solution, and after stirring for 15 minutes the product filtered. This crude product was purified by flash chromatography on a column of silica gel, eluting with a 1:1 mixture of ethyl acetate and hexane, and the pure title product (211 mg) was obtained. m.p. 154°-155° C.
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[CH:12]=[C:11]([F:15])[CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:16]#[N:17])=[CH:4][N:3]=1.[CH:18]1([CH:21]([NH2:23])[CH3:22])[CH2:20][CH2:19]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:18]1([CH:21]([NH:23][C:2]2[C:14]3[C:13]4[CH:12]=[C:11]([F:15])[CH:10]=[CH:9][C:8]=4[NH:7][C:6]=3[C:5]([C:16]#[N:17])=[CH:4][N:3]=2)[CH3:22])[CH2:20][CH2:19]1
Reactant: CC(N)C1CC1
Reactant: N#Cc1cnc(Cl)c2c1[nH]c1ccc(F)cc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(Nc1ncc(C#N)c2[nH]c3ccc(F)cc3c12)C1CC1
Temperature: 85 °C
Reaction time: 20 h

Procedure:
1-Chloro-8-fluoro-5H-pyrido[4,3-b]indole-4-carbonitrile (400 mg, 1.63 mmol), 1-cyclopropylethanamine (594 mg, 4.89 mmol), Pd2(dba)3 (74.6 mg, 0.081 mmol), BINAP (152 mg, 0.24 mmol), and sodium tert-butoxide (782 mg, 8.14 mmol) were placed in a sealed tube. The mixture was evacuated and backfilled with argon three times. Fully degassed DME (8.1 ml) was added. The tube was sealed and the reaction was heated to 85° C. and stirred for 20 hrs. The reaction was cooled to ambient temperature, concentrated in vacuo, and directly purified via flash chromatography to afford the title compound. LRMS (APCI) calc'd for (C17H16FN4) [M+H]+, 295.1. found 295.0.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12](N)=[CH:11][CH:10]=[CH:9]2)=[N+:2]=[N-:3].S(=O)(=O)(O)[OH:16].N([O-])=O.[Na+]>O>[N:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[OH:16])[CH:7]=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1cccc2cccc(N)c12
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1cccc2cccc(O)c12

Procedure:
A sample of 8-azido-1-naphthylamine (0.368 g., 0.02 mole) was dissolved in warm, dilute sulfuric acid (3 ml. of conc. H2SO4 diluted with 30 ml. of water). The solution was cooled to O°C. and diazotized with a solution of NaNO2 (160 mg., 0.023 mole) in 2 ml. of water. The excess of nitrous acid was destroyed by the addition of urea. The yellow solution of the diazonium salt was diluted with 100 ml. of water and heated at 60°for 1.5 hr. The precipitated material was washed with water, dried and filtered through activated charcoal. Removal of ether left a residue which weighed 35 mg. Recrystallization from petroleum ether gave 1-azido-8-hydroxynaphthalene in the form of pale yellow needles (20 mg., 5.4 percent), m.p. 65°C.-67°C.
Reaction SMILES: [C:1]([C:4](=[CH:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=1)[C:5]([NH:7][CH2:8][CH2:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6])(=O)[CH3:2].Cl.[C:33]([NH2:36])(=[NH:35])[CH3:34].C([O-])(=O)C.[Na+].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CN(C=O)C>[Cl:31][C:26]1[CH:25]=[C:24]([C:23]2[C:4]([C:5]([NH:7][CH2:8][CH2:9][CH:10]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:6])=[C:1]([CH3:2])[N:36]=[C:33]([CH3:34])[N:35]=2)[CH:29]=[C:28]([Cl:30])[CH:27]=1
Reactant: CC(=O)C(=Cc1cc(Cl)cc(Cl)c1)C(=O)NCCC(c1ccccc1)c1ccccc1
Reactant: CC(=N)N
Agent: CC(=O)[O-]
Agent: Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CN(C)C=O
Product: Cc1nc(C)c(C(=O)NCCC(c2ccccc2)c2ccccc2)c(-c2cc(Cl)cc(Cl)c2)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
111 mg (0.246 mmol) of 2-acetyl-3-(3,5-dichlorophenyl)-N-(3,3-diphenylpropyl) acrylamide was dissolved in 5 ml of DMF. 34.9 mg (0.369 mmol) of acetamidine hydrochloride and 24.2 mg of (0.295 mmol) of sodium acetate were added thereto and stirred at 100° C. overnight. After the solvent was evaporated under reduced pressure, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was dissolved in 10 ml of toluene. 112 mg (0.492 mmol) of DDQ was added thereto and stirred at 100° C. overnight. After filtration of insoluble matters and evaporation of the solvent under reduced pressure, the filtrate was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1 to 1/1) to obtain the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[CH:4][C:3]=1[CH:9]=[O:10].[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C>[N:11]([C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[CH:4][C:3]=1[CH:9]=[O:10])=[N+:12]=[N-:13]
Reactant: O=Cc1cncc(Cl)c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1c(Cl)cncc1C=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
A mixture of 4,5-dichloropyridine-3-carbaldehyde (6.78 g, 38.5 mmol) and sodium azide (2.62 g, 40.4 mmol) in DMF (25 mL) was stirred at room temperature for 18 hours. The reaction mixture was quenched with brine (250 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-40% ethyl acetate in pentane) to afford the title compound as a yellow solid (6.7 g, 96% yield). 1H NMR (400 MHz, CDCl3): δ 10.36 (s, 1H), 8.84 (s, 1H), 8.65 (s, 1H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][N:15]=1)C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)CC([CH2:23][C:24]([OH:26])=O)(C(O)=O)O>O1CCCC1.ICI.C[Li]>[O:26]1[CH2:24][CH:23]1[C:5]1[CH:4]=[CH:3][C:2]([O:1][C:8]2[CH:9]=[CH:10][CH:13]=[CH:14][N:15]=2)=[CH:7][CH:6]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: O=Cc1ccnc(Oc2ccccc2)c1
Agent: [Li]C
Solvent: ICI
Solvent: C1CCOC1
Product: c1ccc(Oc2ccc(C3CO3)cc2)nc1
Reaction time: 1 h

Procedure:
To a solution of 2-phenoxyisonicotinaldehyde (378 mg) in tetrahydrofuran (4 ml), 0.228 ml of diiodomethane and 3.8 ml of methyllithium (1.0M diethyl ether solution) were added under ice-cooling, and the reaction solution was stirred at the same temperature for 1 hour. To the reaction solution was added 10% aqueous citric acid, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (98:2-50/50)) to afford the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:17]=[C:16]3[C:10]([CH2:11][CH2:12][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:15]3)=[N:9]2)=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1.CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:25]1([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:17]=[C:16]4[C:10]([CH2:11][CH2:12][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:15]4)=[N:9]3)=[CH:4][CH:3]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(Br)cc3)nc2CC1
Reactant: C1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(N4CCCCC4)cc3)nc2CC1

Procedure:
A solution of 1,1-dimethylethyl 2-(4-bromophenyl)-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (may be prepared as described in Description 12) (150 mg, 0.38 mmol), piperidine (76 μl, 0.76 mmol), [2′-(dicyclohexylphosphanyl)-2-biphenylyl]dimethylamine (24 mg, 0.06 mmol), tris(dibenzylideneacetone)dipalladium(0) (174 mg, 0.20 mmol), and sodium tert-butoxide (73 mg, 0.76 mmol) in dioxan (4.5 ml) was heated at 120° C. in the microwave (normal absorption) for 30 min. The reaction mixture was diluted with methanol and then purified by SCX, eluting with methanol and then 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo. The crude product was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate in hexane (0-50%) to afford the title compound. MS (ES+) m/e 397 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21]([NH:26][C@H:27]1[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][CH2:28]1)[CH:20]=[CH:19]2)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[O:6])[CH:2]=[CH2:3]>CO.[Pd]>[C@H:27]1([NH:26][C:21]2[CH:20]=[CH:19][C:18]3[C:23](=[CH:24][CH:25]=[C:16]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([NH:7][C:8]4[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=4)=[O:6])[CH:17]=3)[N:22]=2)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1
Reactant: C=CCN(C(=O)Nc1ccc(OC)cc1)c1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Agent: [Pd]
Solvent: CO
Product: CCCN(C(=O)Nc1ccc(OC)cc1)c1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
Allyl-1-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-3-(4-methoxy-phenyl)-urea (38 mg, 0.08 mmol) was dissolved in methanol (2 mL). Pd/C (10 mg, 10%) was added and the reaction mixture was stirred under an atmosphere of hydrogen at ambient temperature for 1 h. Then the mixture was filtered, the filter washed with methanol and the filtrate concentrated and dried under high vacuum. The title compound (12 mg, 32%) was obtained as a yellow solid; MS: (ISP) 467.8 [(M+H)+].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18]([O:26]C(OC)=O)=[CH:17][C:16]=2[NH:31][C:32]([CH:34]2[O:39][C:38]3[CH:40]=[CH:41][C:42]([C:44]#[N:45])=[CH:43][C:37]=3[N:36](C(OCC)=O)[CH2:35]2)=[O:33])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[C:44]([C:42]1[CH:41]=[CH:40][C:38]2[O:39][CH:34]([C:32]([NH:31][C:16]3[CH:17]=[C:18]([OH:26])[C:19]([CH:21]4[CH2:22][CH2:23][CH2:24][CH2:25]4)=[CH:20][C:15]=3[CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[O:33])[CH2:35][NH:36][C:37]=2[CH:43]=1)#[N:45]
Reactant: CCOC(=O)N1CC(C(=O)Nc2cc(OC(=O)OC)c(C3CCCC3)cc2CN2CCN(C(=O)OC(C)(C)C)CC2)Oc2ccc(C#N)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)NCC(C(=O)Nc1cc(O)c(C3CCCC3)cc1CN1CCNCC1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.5 %

Procedure:
To a solution of ethyl 2-(2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-4-cyclopentyl-5-(methoxycarbonyloxy)phenylcarbamoyl)-6-cyano-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (15 mg, 0.022 mmol) in dichloromethane (500 μL) was added TFA (3 μL, 0.04 mmol) and the reaction was stirred overnight at room temperature. The reaction was quenched with aqueous NaHCO3 and the layers separated. The aqueous layer was extracted with dichloromethane, dried over MgSO4, filtered and concentrated. The crude product was dissolved in methanol and 1M NaOH and the reaction was heated at reflux for 5 min. The reaction was quenched with 1M HCl and the aqueous layer was extracted with dichloromethane. The organic layer was dried over MgSO4, filtered and concentrated. Purification by HPLC (10-99% CH3CN/0.05% TFA) provided 6-cyano-N-[4-cyclopentyl-5-hydroxy-2-(piperazin-1-ylmethyl)phenyl]-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide (3 mg, 24% yield). LC/MS m/z 462.5 [M+H]+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Br[C:15]1[C:20](=[O:21])[N:19]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:25][CH:24]=2)[C:18]([CH2:37][CH2:38][CH2:39][CH3:40])=[N:17][C:16]=1[CH3:41]>O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C.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]>[CH2:37]([C:18]1[N:19]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:27][CH:28]=2)[C:20](=[O:21])[C:15]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[C:16]([CH3:41])[N:17]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Reactant: CCCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)c(-c2ccc(OC(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
A mixture of (4-isopropoxyphenyl)boronic acid (0.31 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.05 g) and 4′-[(5-bromo-2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.5 g) in 1,4-dioxane (10 mL) and 2 M cesium carbonate (2 mL) was stirred overnight at 100° C. under an argon atmosphere. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.56 g, 99%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Br:19])=[N:8][C:9]([CH3:12])=[N:10][CH:11]=1)=[O:5])C.C(O)C>O>[Br:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=[C:9]([CH3:12])[N:8]=1
Reactant: CCOC(=O)c1cnc(C)nc1-c1ccccc1Br
Solvent: CCO
Solvent: O
Product: Cc1ncc(C(=O)O)c(-c2ccccc2Br)n1
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a solution of 8.3 g (25.8 mmol) 4-(2-bromo-phenyl)-2-methyl-pyrimidine-5-carboxylic acid ethyl ester in 10 ml ethanol 1.55 g (38.6 mmol) NaOH in 20 ml H2O was added. After stirring for 1 hr., the reaction mixture was washed with 100 ml diethylether. The pH of the aqueous phase was adjusted to 1 with 25% HCl and than extracted twice with 200 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtrated and evaporated to give 7.0 g (92%) 4-(2-bromo-phenyl)-2-methyl-pyrimidine-5-carboxylic acid as a pale yellow foam.
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]([NH:19][CH2:20][C:21]([OH:23])=O)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].CN1CCOCC1.[NH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][N:38]=[C:39]([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44]>O1CCCC1>[CH3:53][C:51]([CH3:54])([O:50][C:49]([NH:48][C:39]([NH:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][NH:31][C:21](=[O:23])[CH2:20][NH:19][C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])=[N:40][C:41]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:47])=[O:55])[CH3:52]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(=NCCCCCCN)NC(=O)OC(C)(C)C
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N=C(NCCCCCCNC(=O)CNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A solution of 1.6 g (14×10-3 mol) of isobutyl chloroformate in 5 ml of tetrahydrofuran is added dropwise to a solution, cooled to -30° C., of 3 g (14×10-3 mol) of carbobenzyloxyglycine and 2.8 g (28×10-3 mol) of N-methylmorpholine in 50 ml of tetrahydrofuran. The reaction medium is stirred for 0.5 hour and a solution of 5.4 g (14×10-3 mol) of bis(1,1-dimethylethyl) [[(6-aminohexyl)imino]methylene]biscarbamate in 20 ml of tetrahydrofuran is added. Stirring is continued for 2 hours at -30° C. and then for 24 hours at room temperature. After filtration of the reaction medium and evaporation of the filtrate under reduced pressure, the residue obtained is purified by chromatography on silica using an ethyl acetate/methylcyclohexane mixture (1/1 v/v) as the eluent to give 7.16 g (yield: 91%) of the expected product in the form of an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:14]([O-])=O)[N:5]=1)[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:14][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH:12]=[CH:13][C:4]([O:3][CH2:1][CH3:2])=[N:5]2
Reactant: [H][H]
Reactant: CCOc1ccc2c([N+](=O)[O-])cccc2n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1ccc2c(N)cccc2n1

Procedure:
860 mg (3.9 mmol) of 2-ethoxy-5-nitroquinoline is stirred in 25 ml of ethyl acetate in the presence of 235 mg of 10% Pd—C for 4.5 hours in a hydrogen atmosphere. The batch is filtered, and the filtrate is concentrated by evaporation: 720 mg of a light yellow oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]C(Br)(Br)Br.O[CH:26]([C:28]1[O:29][C:30](=[O:45])[C:31]2[C:36]([C:37]=1[C:38]1[CH:39]=[C:40]([CH3:44])[CH:41]=[CH:42][CH:43]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:27]>C(Cl)Cl>[Br:20][CH:26]([C:28]1[O:29][C:30](=[O:45])[C:31]2[C:36]([C:37]=1[C:38]1[CH:39]=[C:40]([CH3:44])[CH:41]=[CH:42][CH:43]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:27]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cccc(-c2c(C(C)O)oc(=O)c3ccccc23)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cccc(-c2c(C(C)Br)oc(=O)c3ccccc23)c1
Temperature: 25 °C
Yield: 18.2 %

Procedure:
Triphenylphosphine (365 mg, 1.39 mmol) and perbromomethane (461 mg, 1.39 mmol) were was added to a solution of 3-(1-hydroxyethyl)-4-m-tolyl-1H-isochromen-1-one (intermediate B6, 300 mg, 1.07 mmol) in DCM (2.2 ml), and the resulting mixture was stirred at RT. The reaction product was then purified on the silica Biotage SNAP 50 g, eluting with a gradient of hexane and EtOAc to give the title compound (67 mg, 18.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].[C:38](O)(=[O:41])[CH2:39][CH3:40]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH:22][C:38](=[O:41])[CH2:39][CH3:40])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:27][CH2:26]1)=[O:24]
Reactant: CCC(=O)O
Reactant: NS(=O)(=O)c1cnn2c(Nc3cc(Cl)ccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Product: CCC(=O)NS(=O)(=O)c1cnn2c(Nc3cc(Cl)ccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 90.7 %

Procedure:
Using 7-(2,5-dichlorophenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.050 g, 0.089 mmol) obtained in step 5 and propionic acid (0.033 mL, 0.444 mmol) instead of cyclopropanecarboxylic acid, and in the same manner as in Example 1 step 6, the title compound (0.050 g, 92%) was obtained.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=1)(=[O:3])[NH2:2].[OH-].[Na+].Cl>CO>[C:1]([C:4]1[C:5]([NH:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=1)(=[O:3])[NH2:2]
Reactant: COC(=O)c1ccc(Nc2nc(Cl)ccc2C(N)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1ccc(Cl)nc1Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl 4-(3-carbamoyl-6-chloropyridin-2-ylamino)benzoate was dissolved in 20 mL of MeOH, treated with 10 mL of 30% NaOH, and stirred at rt for 3 h. The reaction mixture was acidified with 1N HCl and the resulting solid was filtered and air dried to give 1.43 g of 4-(3-carbamoyl-6-chloropyridin-2-ylamino)benzoic acid as a yellow solid. LCMS: (M+H)+=292.06, 294.00 (Cl pattern).