Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH2:16][CH2:17][O:18][Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:4][N:5]1[CH:13]=[N:12][C:11]2[C:10](=[O:14])[NH:9][C:8]([NH2:15])=[N:7][C:6]1=2.[C:36](Cl)(=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53].CO.C(=O)([O-])O.[Na+]>N1C=CC=CC=1.ClCCl>[C:36]([O:1][CH2:2][C@H:3]([CH2:16][CH2:17][O:18][Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:4][N:5]1[CH:13]=[N:12][C:11]2[C:10](=[O:14])[NH:9][C:8]([NH2:15])=[N:7][C:6]1=2)(=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC(C)(C)[Si](OCC[C@@H](CO)Cn1cnc2c(=O)[nH]c(N)nc21)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Cn1cnc2c(=O)[nH]c(N)nc21
Reaction time: 1 h

Procedure:
(R)-9-[2-Hydroxymethyl 4-(t-butyldiphenylsilyloxy)butyl]guanine (2.31 g, 5 mmole) was coevaporated with dry pyridine twice and dissolved in pyridine (20 ml). To the solution was slowly added dropwise stearoyl chloride (1.86 ml, 5.5 mmole, technical grade) in dichloromethane (2 ml) at −5° C. The reaction was kept at the same temperature for 1 hr and then at 5° C. for 2 hr. The reaction was monitored by TLC. Additional stearoyl chloride (0.29 ml) at −5° C. was added due to incompletion of reaction. After 30 min at 5° C., methanol (3 ml) was added and the reaction mixture stirred for 20 min. It was then poured into aqueous sodium hydrogen carbonate solution, and extracted with dichloromethane. The organic phase was dried and the product purified by silica gel column chromatography with stepwise increasing MeOH, eluting with 3.5% MeOH in CH2Cl2. (Yield 2.7 g).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:48][C@H:49]([CH:62]1[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]1)[C:50]1[CH:55]=[CH:54][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:52][CH:51]=1>CN(C=O)C>[CH:62]1([C@@H:49]([NH:48][C:8]([C:7]2[C:2]([OH:1])=[N:3][C:4]([N:11]3[CH:15]=[CH:14][CH:13]=[N:12]3)=[N:5][CH:6]=2)=[O:10])[C:50]2[CH:51]=[CH:52][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:54][CH:55]=2)[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67]1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Reactant: CCOP(C)(=O)c1ccc([C@H](N)C2CCCCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOP(C)(=O)c1ccc([C@H](NC(=O)c2cnc(-n3cccn3)nc2O)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 49 %

Procedure:
To a stirred solution of 4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid, 8-b, (1.187 g, 5.76 mmol) and Et3N (1.75 mg, 17.3 mmol) in DMF (15 mL) was added HATU (2.62 mg, 6.9 mmol). The mixture was stirred for 5 min at room temperature and then compound 26-e (1.7 g, 5.76 mmol) was added. The resulting mixture was stirred at room temperature for 15 hour. The mixture was then concentrated under vacuum and the residue was taken into ethyl acetate followed by washing with 1N HCl. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel chromatography (ethyl acetate:MeOH=5/1) to provide the product, 26-f, (1.05 g, 49%).
Reaction SMILES: O=C1C2(C3C(=CC4OCCOC=4C=3)OC2)C2C(=CC=CC=2)N1C[C:24]1[C:29]([C:30]([OH:32])=O)=[CH:28][CH:27]=[CH:26][N:25]=1.Cl.CN.O[N:37]1C2C=CC=CC=2N=N1.CN1CCOCC1>O.CN(C)C=O>[N:25]1[CH:26]=[CH:27][CH:28]=[C:29]([C:30]([NH2:37])=[O:32])[CH:24]=1
Reactant: O=C(O)c1cccnc1CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Reactant: On1nnc2ccccc21
Agent: CN
Agent: Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 335.7 %

Procedure:
A 50 mL round-bottom flask was charged with 2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxylic acid (0.43 g, 1.0 mmol), methylamine hydrochloride (0.14 g, 2.0 mmol), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (0.26 g, 1.4 mmol), 1-hydroxybenzotriazole (0.20 g, 1.5 mmol), N-methylmorpholine (0.4 mL, 3.6 mmol) and N,N-dimethylformamide (7 mL). The reaction mixture was stirred under nitrogen at ambient temperature for 20 h, and poured into water (200 mL). The solid was collected by filtration, washed with water, dried and purified by column chromatography and eluted with a 0% to 50% gradient of ethyl acetate in dichloromethane to afford N-methyl-2-[2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxamide (0.41 g, 92%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 8.43 (d, J=4.8 Hz, 1H), 7.85 (d, J=7.7 Hz, 1H), 7.36 (dd, J=7.5, 5.0 Hz, 1H), 7.20-7.07 (m, 2H), 6.95 (t, J=7.5, 1H), 6.81 (d, J=7.8 Hz, 1H), 6.46 (d, J=1.2 Hz, 1H), 6.43 (d, J=1.2 Hz, 1H), 5.16 (ABq, 2H), 4.70 (ABq, 2H), 4.20-4.05 (m, 4H), 2.77 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.3, 167.6, 154.9, 152.7, 150.1, 144.5, 143.3, 138.1, 136.2, 132.5, 131.6, 129.0, 123.7, 123.1, 122.9, 122.2, 112.4, 109.6, 99.0, 79.7, 64.6, 64.1, 57.7, 43.3, 26.5; MS (ES+) m/z 443.9 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([NH:14][C:15]3([C:21]#[CH:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:10]([CH3:13])[N:11]=2)[C:6](=[O:23])[C:5]([C:24]([O:26]CC)=[O:25])=[CH:4]1)[CH3:2].[OH-].[Na+].C(#N)C>O1CCOCC1.O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([NH:14][C:15]3([C:21]#[CH:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:10]([CH3:13])[N:11]=2)[C:6](=[O:23])[C:5]([C:24]([OH:26])=[O:25])=[CH:4]1)[CH3:2]
Reactant: C#CC1(Nc2cc3c(=O)c(C(=O)OCC)cn(CC)c3nc2C)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CC#N
Product: C#CC1(Nc2cc3c(=O)c(C(=O)O)cn(CC)c3nc2C)CCCCC1
Temperature: 60 °C

Procedure:
Ethyl 1-ethyl-6-(1-ethynylcyclohexylamino)-7-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylate (10 mg) was dissolved in 5 ml of dioxane, 2.5 equivalents of a 1 N NaOH solution were added, and the mixture was heated at 60° C. for 4 h. Removal of the solvent in vacuo was followed by chromatography on an HPLC system to purify the product. The pure product was isolated from the reaction solution by chromatography on an HPLC system. This entailed use of a Merck Purospher-RP18 column and an acetonitrile:water mixture as eluent; the initial acetonitrile content was 15% and rose to 95% over the course of 20 minutes.
Reaction SMILES: B(F)(F)F.[O:5]=[C:6]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]([C:14]([F:17])([F:16])[F:15])=[C:8]([C:18](OCC)=[O:19])[S:7]1.[H-].C([Al+]CC(C)C)C(C)C.[Na].[K]>C1(C)C=CC=CC=1>[OH:19][CH2:18][C:8]1[S:7][C:6](=[O:5])[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]=1[C:14]([F:16])([F:17])[F:15]
Reactant: C=CCn1c(C(F)(F)F)c(C(=O)OCC)sc1=O
Agent: CC(C)C[Al+]CC(C)C
Agent: FB(F)F
Agent: [H-]
Solvent: Cc1ccccc1
Product: C=CCn1c(C(F)(F)F)c(CO)sc1=O
Temperature: -65 °C
Yield: 54.4 %

Procedure:
4.3 ml of boron trifluoride ethereate were introduced at -65° C. into a solution of 8.65 g of the product of Step A in 100 ml of toluene and the mixture was stirred at -65° C. Then, 155 ml of 0.5M solution of diisobutylaluminium hydride in toluene were introduced and the mixture was poured into an iced molar solution of sodium and potassium double tartrate followed by stirring for 2 hours. After decanting and extraction with ethyl acetate, the extracts were washed with water and with a saturated solution of sodium chloride, dried, filtered and concentrated. The residue was chromatographed on silica and elution with a hexane-ethyl acetate mixture (7-3) yielded 4 g of the expected product with a Rf=0.25.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+].O>CS(C)=O>[CH2:8]([N:1]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(CN(Cc2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A stirred solution of 93.1 g (1 mole) of aniline, 342.1 g (2 mole) of benzyl bromide, and 252 g (3 mole) of sodium bicarbonate in dimethylsulfoxide is heated at 90° C. for three hours. After cooling to room temperature, the reaction mixture is poured into a four-fold excess of water, and the aqueous solution is extracted with methylene chloride. The combined organics are filtered through cotton and evaporated to yield N,N-dibenzylaniline, which is purified by flash chromatography.
Reaction SMILES: C(O)(=O)C.O.[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2([C:29]([F:32])([F:31])[F:30])[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]([Cl:28])=[C:23]([N+:25]([O-])=O)[CH:24]=3)[CH2:15]2)[CH:10]=[C:11]([Cl:13])[CH:12]=1>[Fe].C(O)C>[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2([C:29]([F:30])([F:32])[F:31])[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]([Cl:28])=[C:23]([CH:24]=3)[NH2:25])[CH2:15]2)[CH:10]=[C:11]([Cl:13])[CH:12]=1
Reactant: O=[N+]([O-])c1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Cl
Agent: [Fe]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Cl
Temperature: 75 °C
Reaction time: 0.83 h
Yield: 64.9 %

Procedure:
An iron powder (3.46 g) was added to a mixture of acetic acid (0.38 g), water (15 ml) and ethanol (30 mL) at room temperature, and thereto was added 5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-chloronitrobenzene (2.73 g) obtained by Reference Production Example 19 at 75° C. After stirring at 75° C. for 50 minutes, the reaction mixture was filtrated and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-chloroaniline (1.65 g).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][NH:18][CH2:17][C:16]=3[CH:22]=2)[CH:9]=[CH:8][C:6]=1[NH2:7])([O-:4])=[O:3].CCN(C(C)C)C(C)C.Cl[C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34]>ClCCl>[NH2:7][C:6]1[CH:8]=[CH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][N:18]([C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34])[CH2:17][C:16]=3[CH:22]=2)=[CH:11][C:5]=1[N+:2]([O-:4])=[O:3]
Reactant: C=CCOC(=O)Cl
Reactant: Nc1ccc(-c2ccc3c(c2)CNCCO3)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)N1CCOc2ccc(-c3ccc(N)c([N+](=O)[O-])c3)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.5 %

Procedure:
2-nitro-4-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)aniline hydrochloride salt (3.61 g, 11.2 mmol) and DIPEA (5.2 mL, 30 mmol) were taken into dichloromethane (50 mL) followed by dropwise addition of allyl chloroformate (1.23 mL, 11.2 mmol) over 5 minutes. The mixture was allowed to stir 30 minutes at room temperature then concentrated. The residue was partitioned with ethyl acetate and 10% aqueous citric acid and the organic solution washed with brine then dried over anhydrous sodium sulfate, filtered and concentrated to give prop-2-en-1-yl 7-(4-amino-3-nitrophenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (4.2 g, 100% yield) as a red amorphous residue. MS (EI) for C19H19N3O5: 370 (MH1).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[N:23][C:24](S(C)(=O)=O)=[N:25][CH:26]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[CH:31]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.[OH-].[K+].O>CN1CCCC1=O>[Cl:19][C:17]1[CH:18]=[C:13]2[C:12]([CH2:20][C:21]3[CH:26]=[N:25][C:24]([NH:37][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[N:23][CH:22]=3)=[CH:11][NH:10][C:14]2=[N:15][CH:16]=1
Reactant: NC1CCCCC1
Reactant: CS(=O)(=O)c1ncc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Clc1cnc2[nH]cc(Cc3cnc(NC4CCCCC4)nc3)c2c1
Temperature: 155 °C
Yield: 25.7 %

Procedure:
In a microwave vial, to 1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (37, 60 mg, 0.13 mmol) in 1.0 mL of N-methylpyrrolidinone, cyclohexanamine (62, 0.20 g, 2.0 mmol) is added. The reaction is heated at 155° C. for 25 minutes in a microwave, then potassium hydroxide (1.0 mL, 1.00 M in water, 1.0 mmol) is added and the reaction heated at 95° C. for 15 minutes in a microwave. The reaction is poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are collected and concentrated under vacuum to provide the desired compound (P-3001, 11.4 mg). MS (ESI) [M+H+]+=341.9.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)=O)(C)(C)C.Cl[C:19]1[C:20]([C:33]#[N:34])=[N:21][CH:22]=[C:23](/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CO>[CH:25](/[C:23]1[CH:22]=[N:21][C:20]2[C:19]([CH:24]=1)=[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]1=[N:8][C:33]=2[NH2:34])=[CH:26]\[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B(O)O
Reactant: N#Cc1ncc(/C=C/c2ccccc2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CO
Product: Nc1nc2ccccc2c2cc(/C=C/c3ccccc3)cnc12
Temperature: 25 °C

Procedure:
A solution of 2-(tert-butoxycarbonylamino)phenylboronic acid (1.0 eq.) and (E)-3-chloro-5-styrylpicolinonitrile (from step 1) (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (2.0 eq.) in toluene/ethanol (2:1, 0.03 M) was stirred at 100° C. overnight. After cooling to ambient temperature, the reaction content was diluted with methanol. The insoluble solids were filtered off, and the filtrate was concentrated en vacuo to obtain a crude residue. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give (E)-2-styrylbenzo[f][1,7]naphthyridin-5-amine as a brown solid. 1H NMR (dmso-d6): δ 9.22 (d, 1H), 9.06 (d, 1H), 8.51 (d, 1H), 7.78 (d, 1H), 7.66 (d, 2H), 7.46-7.56 (m, 3H), 7.70 (t, 2H), 7.26-7.32 (m, 2H), 7.08 (bs, 2H). LRMS [M+H]=298.2.
Reaction SMILES: O1CCCC1.[I:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.[OH-].[Na+]>C(OCC)(=O)C>[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[N:24]1[CH2:25][CH2:26][N:27]([C:11]([C:10]2[CH:14]=[CH:15][C:7]([I:6])=[CH:8][CH:9]=2)=[O:12])[CH2:28][CH2:29]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.4 %

Procedure:
To tetrahydrofuran (60 mL) were added 4-iodobenzoyl chloride (5 g), 1-(2,4-dimethylphenyl)piperazine (3.6 g) and 1N aqueous sodium hydroxide solution (20 mL), and the mixture was stirred at room temperature overnight. Ethyl acetate was added for partitioning, the organic layer was washed with saturated brine, and the solvent was evaporated. The title compound (8 g) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[N:6][CH:7]=1.[CH2:17]([O:19][C:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)=[O:21])[CH3:18].C(=O)([O-])[O-].[K+].[K+].O>COCCOC.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.CN(C=O)C>[C:10]1([C:9]([NH:8][C:4]2[CH:3]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([C:20]([O:19][CH2:17][CH3:18])=[O:21])=[CH:23][CH:24]=3)[CH:7]=[N:6][CH:5]=2)=[O:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Nc1cncc(Br)c1)c1ccccc1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
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: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: COCCOC
Product: CCOC(=O)c1ccc(-c2cncc(NC(=O)c3ccccc3)c2)cc1
Temperature: 85 °C
Reaction time: 12 h

Procedure:
At 50° C., 5.14 g (18.2 mmol) of N-(5-bromopyridin-3-yl)benzamide, 5.40 g (27.8 mmol) of 4-ethoxycarbonylphenylboronic acid and 5.03 g (36.4 mmol) of potassium carbonate were dissolved in 30 ml of 1,2-dimethoxyethane, 9 ml of water and 65 ml of DMF. The mixture was flushed with argon, 105 mg (0.09 mmol) of tetrakis(triphenylphosphine)palladium(0) were added and the mixture was stirred at 85° C. for 12 h. The reaction mixture was concentrated slightly on a rotary evaporator, diluted with water and extracted with dichloromethane. The organic phase was concentrated under reduced pressure and the residue was triturated with methyl tert-butyl ether, the solid was filtered off and the filtrate was purified by column chromatography (cyclohexane/ethyl acetate 2:1→1:1). The separated solid and the appropriate fraction from the chromatography were combined. Yield: 4.6 g (60% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[N:10]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[C:27](O)=[O:28])=[CH:22][CH:21]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]([O:46][CH3:47])=[O:45])=[CH:40][CH:39]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[N:10]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([CH:26]([CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[C:27]([NH:36][CH2:37][C:38]4[CH:39]=[CH:40][C:41]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:43]=4)=[O:28])=[CH:24][CH:25]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)C(c1ccc(Cn2nc(-c3ccc(Cl)cc3)c3ccccc3c2=O)cc1)C1CCCC1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CNC(=O)C(c2ccc(Cn3nc(-c4ccc(Cl)cc4)c4ccccc4c3=O)cc2)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60 mg (0.127 mmol) of (4-{[4-(4-chlorophenyl)-1-oxophthalazin-2(1H)-yl]methyl}phenyl)(cyclopentyl)acetic acid (Example 65A) were dissolved in 0.6 ml of dichloromethane, and 26 mg (0.127 mmol) of methyl 4-(aminomethyl)benzenecarboxylate hydrochloride, 19 mg (0.140 mmol) of 1-hydroxy-1H-benzotriazole hydrate, 28 mg (0.146 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 28 mg (0.273 mmol) of triethylamine were added in succession. The reaction mixture was stirred at room temperature overnight. 1 N hydrochloric acid was then added, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The residue was purified by preparative HPLC. This gave 36 mg (46% of theory) of the title compound.
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:16][C:12]3([CH2:15][O:14][CH2:13]3)[CH2:11]2)(=O)=O)=CC=1.[Mg].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+].[C:43]([OH:48])(=[O:47])[C:44]([OH:46])=[O:45]>CO.C(O)C.C(OCC)C>[C:43]([OH:48])(=[O:47])[C:44]([OH:46])=[O:45].[CH2:13]1[C:12]2([CH2:16][NH:10][CH2:11]2)[CH2:15][O:14]1.[CH2:13]1[C:12]2([CH2:16][NH:10][CH2:11]2)[CH2:15][O:14]1
Reactant: Cc1ccc(S(=O)(=O)N2CC3(COC3)C2)cc1
Agent: O=C(O)C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: C1NCC12COC2
Reaction time: 0.5 h

Procedure:
6-(Toluene-4-sulfonyl)-2-oxa-6-azaspiro[3.3]heptane (510 mg, 2 mmol) and magnesium granular (336 mg, 14 mmol) were sonicated for one hour in methanol (100 ml). Almost all solvent was removed from the grey reaction mixture on a rotary evaporator to give a viscous grey residue. Diethyl ether (10 ml) and sodium sulfate decahydrate (1 g) were added and the resulting light grey mixture was stirred vigorously for 30 minutes before filtration. The filtrate was dried over anhydrous sodium sulfate and anhydrous oxalic acid (90 mg, 1 mmol) dissolved in Ethanol (˜0.5 mL) was added to the organic phase. A thick white precipitate formed instantly. It was filtered off and dried under vacuum to give 2-oxa-6-azaspiro[3.3]heptane hemioxalate (140 mg, 37%) off-white solid. 1H NMR (300 MHz, CDCl3) δ 4.64 (s, 4H), 4.11 (s, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:16]1[C:24]([OH:25])=[CH:23][C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=1)([CH2:14]O)[C:5](=[O:13])[N:6]2CO.C(P(CCCC)CCCC)CCC.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[OH-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:24]3[O:25][CH2:14]1)[C:5](=[O:13])[NH:6]2
Reactant: O=C1N(CO)c2cccc(Cl)c2C1(CO)c1cc2c(cc1O)OCO2
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C1Nc2cccc(Cl)c2C12COc1cc3c(cc12)OCO3
Temperature: 0 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
To a solution of 4-chloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-bis(hydroxymethyl)-1,3-dihydro-2H-indol-2-one (3.63 g, 10.0 mmol) in anhydrous tetrahydrofuran (100.0 mL) was added tributylphosphine (2.53 g, 12.5 mmol) at 0° C. followed by the solution of di-tert-butyl azodicarboxylate (2.88 g, 12.5 mmol) in anhydrous tetrahydrofuran (25.0 mL). The reaction solution was stirred at 0° C. for 1 h followed by the addition of ammonium hydroxide (100.0 mL). The reaction mixture was continued to stir for another 2 h. The reaction was quenched with 10% aqueous solution of hydrochloric acid (100.0 mL). The reaction solution was extracted with ethyl acetate (3×100.0 mL). The combined organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified by flash chromatography with ethyl acetate in hexanes to afford 4′-chlorospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.98 g, 31%) as a colourless solid: mp 175-185° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.24 (t, J=8.0 Hz, 1H), 6.94 (d, J=8.2 Hz, 1H), 6.86 (d, J=7.1 Hz, 1H), 6.59 (s, 1H), 6.28 (s, 1H), 5.90 (d, J=2.5 Hz, 2H), 4.74 (ABq, J=9.5 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 178.4, 157.0, 148.8, 144.2, 141.9, 130.9, 130.3, 129.2, 123.0, 117.5, 109.4, 103.3, 101.9, 93.3, 77.8, 58.9; MS (ES+) m/z 318.3 (M+1), 316.3 (M+1).
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])=O.C(C([O:22][CH2:23][C:24]([NH2:26])=[S:25])=O)(C)(C)C>CCO>[OH:22][CH2:23][C:24]1[S:25][C:2]([CH3:15])=[C:3]([C:5]2[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=2)[C:8]([O:10][CH3:11])=[O:9])[N:26]=1
Reactant: COC(=O)c1cccc(C(=O)C(C)Br)c1
Reactant: CC(C)(C)C(=O)OCC(N)=S
Solvent: CCO
Product: COC(=O)c1cccc(-c2nc(CO)sc2C)c1
Temperature: 60 °C
Yield: 44.6 %

Procedure:
A solution of methyl 3-(2-bromo-propionyl)-benzoate (2.7 g) and 2-(tert.-butyl-carbonyloxy)thioacetamide (2.1 g) in EtOH (20 mL) was heated at reflux for 8 h. The mixture was partitioned between H2O and AcOEt. The organic layer was dried and evaporated. The residue was dissolved in MeOH (20 ml), NaOMe (0.54 g) was added, and the mixture was heated to 60° C. for 1 h. The mixture was diluted with AcOEt and then washed with 3N HCl and brine. The organic layer was dried and evaporated and the residue was crystallized from AcOEt to give methyl 3-[2-hydroxymethyl-5-methyl-thiazol-4-yl]-benzoate (1.17 g) as white solid.