Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:20]=[CH:19][C:10]3[N:11]=[C:12]([CH2:14][C:15]([NH:17][NH2:18])=[O:16])[S:13][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1([CH3:33])[CH:26]=[CH:25][C:24]([S:27]([N:30]=[C:31]=O)(=[O:29])=[O:28])=[CH:23][CH:22]=1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>O1CCOCC1.CO>[CH3:33][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:30][C:31]2[O:16][C:15]([CH2:14][C:12]3[S:13][C:9]4[CH:8]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:20]=[CH:19][C:10]=4[N:11]=3)=[N:17][N:18]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: NNC(=O)Cc1nc2ccc(-c3ccccc3)cc2s1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)Nc2nnc(Cc3nc4ccc(-c5ccccc5)cc4s3)o2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 11.7 %

Procedure:
To a suspension of 2-(6-phenylbenzo[d]thiazol-2-yl)acetohydrazide (26 mg, 0.092 mmol) (described in WO 2011/074560) in dioxane (0.8 mL) was added p-toluenesulfonyl isocyanate (15 μL, 0.10 mmol), and the reaction mixture stirred for 15 min. 1-Propanephosphonic acid cyclic anhydride (50% in EtOAc) (0.164 mL, 0.275 mmol) was added and the reaction mixture stirred at 105° C. for 18 h. The reaction mixture was allowed to cool to rt, diluted with MeOH then purified by preparative HPLC (RT=8.79 min using Axia Luna 5 u C18 30×100 mm column with flow rate of 40 mL/min over 10 min period. Solvent A=10/90/0.1% ACN/H2O/TFA, Solvent B=90/10/0.1%, 10 to 100% B). The fraction containing product was evaporated to dryness and the residue chromatographed on silica gel eluting with 0 to 10% MeOH/DCM to give Compound 90a (5 mg, 12%) as a white solid. LCMS=1.01 min using analytical method (M), 462.9 (M+H). 1H NMR (400 MHz, CDCl3, 60° C.) δ 8.08-7.99 (m, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.59 (d, J=7.0 Hz, 2H), 7.48-7.39 (m, 2H), 7.36 (t, J=7.0 Hz, 1H), 7.24 (d, J=4.3 Hz, 2H), 4.50-4.44 (m, 2H), 2.37 (s, 3H).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[N:13]([C@@H:14]3[O:20][C@H:19]([CH2:21][OH:22])[C@@H:17]([OH:18])[C@H:15]3[OH:16])[CH:12]=[N:11][C:10]=2[C:23]#[N:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:25]O>>[C:1]1([C:7]#[C:8][C:9]2[N:13]([C@@H:14]3[O:20][C@H:19]([CH2:21][OH:22])[C@@H:17]([OH:18])[C@H:15]3[OH:16])[CH:12]=[N:11][C:10]=2[C:23]([NH2:24])=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1C#Cc1ccccc1
Reactant: OO
Product: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
To a solution of 10 mg (0.03 mmol) of 5-(phenylethyn-1-yl)-1-β-D-ribofuranosylimidazole-4-carbonitrile dissolved in 4 ml of aqueous ammoniamethanol (1:1 V/V) was added 0.2 ml of hydrogen peroxide, and the reaction was carried out with stirring at room temperature for 30 minutes. After the reaction, the solvent was evaporated and the residue was adsorbed onto a silica gel column (1.8×35 cm) and eluted with a 5-20% ethanol-chloroform solvent mixture to obtain 8.4. mg of 5-(phenylethyn-1-yl)-1-β-D-ribofuranosylimidazole-4-carboxamide (yield: 79.6%).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][C:8]1[CH:24]=[CH:23][C:22]2[C:13]3[NH:14][C:15](=[O:21])[C:16]4[N:17]([CH:18]=[CH:19][N:20]=4)[C:12]=3[CH2:11][C:10]=2[CH:9]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[OH2:4].[OH2:21].[CH3:1][N:2]([CH3:6])[C:3](=[O:4])[NH:7][C:8]1[CH:24]=[CH:23][C:22]2[C:13]3[NH:14][C:15](=[O:21])[C:16]4[N:17]([CH:18]=[CH:19][N:20]=4)[C:12]=3[CH2:11][C:10]=2[CH:9]=1
Reactant: Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CN(C)C(=O)Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Product: O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
1.2 ml of dimethylcarbamoyl chloride are added dropwise to 1.5 g of 8-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one and 0.15 g of 4-dimethylaminopyridine in 45 ml of pyridine. After reacting for 5 hours at a temperature in the region of 20° C., 1.2 ml of dimethylcarbamoyl chloride are again added. The reaction is continued overnight at the same temperature and the reaction mixture is then heated at 50° C. for 1 hour. After cooling, the insoluble material is filtered, washed with water and dried. The solid thus obtained is recrystallized from dimethylformamide, washed with water and then dried under partial vacuum (1 mm Hg, 0.13 kPa) at 50° C. There is obtained 0.3 g of 8-(3,3-dimethylureido)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one dihydrate in the form of a pink solid, the melting point of which is greater than 260° C. (Analysis C16H15N5 O2.2H2O, % calculated C: 62.13, H: 4.89, N: 22.64, % found C: 62.2, H: 4.6, N: 22.4).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][C:13]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])=[C:14]([CH3:16])[N:15]=3)[S:10][C:3]=12.[C:25]1([C:31]2[NH:35][NH:34][C:33](=[O:36])[CH:32]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:16][C:14]1[N:15]=[C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[O:36][C:33]3[CH:32]=[C:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[NH:35][N:34]=3)[CH:8]=2)[S:12][C:13]=1[C:17]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:18]
Reactant: O=c1cc(-c2ccccc2)[nH][nH]1
Reactant: Cc1nc(-c2cc3nccc(Cl)c3s2)sc1C(=O)N1CCOCC1
Product: Cc1nc(-c2cc3nccc(Oc4cc(-c5ccccc5)[nH]n4)c3s2)sc1C(=O)N1CCOCC1
Yield: 17 %

Procedure:
The title compound (37 mg, 17%) was prepared from [2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazol-5-yl]-morpholin-4-yl-methanone and 5-Phenyl-1,2-dihydro-pyrazol-3-one by a procedure analogous to Example 16 1. C25H21N5O3S2: APCI m/z 503.5 (pos.); 1H NMR (CD3OD): δ 8.55 (d, 1H, J=5.8 Hz), 8.00 (s, 1H), 7.72 (d, 2H, J=7.1 Hz), 7.46 (t, 2H, J=7.1 Hz), 7.41 (t, 1H, J=7.1 Hz), 7.08 (d, 1H, J=5.8 Hz), 6.53 (s, 1H), 3.71–3.60 (bm, 8H), 2.46 (s, 3H) ppm.
Reaction SMILES: [CH3:1][C@@H:2]1[N:6]2[C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N+:10]([O-])=[CH:9][C:8]=3[N:18]=[C:5]2[N:4]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:3]1.[OH-].[NH4+:27].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl.C(Cl)(Cl)Cl>[NH2:27][C:9]1[C:8]2[N:18]=[C:5]3[N:4]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:3][C@H:2]([CH3:1])[N:6]3[C:7]=2[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)c2nc3c[n+]([O-])c4ccccc4c3n21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: C[C@H]1CN(C(=O)OC(C)(C)C)c2nc3c(N)nc4ccccc4c3n21

Procedure:
A solution of tert-butyl (10S)-10-methyl-9,10-dihydro-8H-imidazo[1′,2′:1,2]imidazo[4,5-c]quinoline-8-carboxylate 5-oxide (1.22 g, 3.58 mmol) in 50 mL of CH2Cl2 was treated with 5 mL of concentrated aqueous ammonium hydroxide and stirred vigorously. p-Toluenesulfonyl chloride (0.68 g, 3.58 mmol) was added in one portion and the reaction became slightly exothermic. The following day the reaction was treated with 5 mL of H2O, and the layers were separated. The organic layer was washed with saturated NaHCO3 solution (2×), then brine. It was dried over Na2SO4, filtered and concentrated to give a crude solid. Chromatography (SiO2, 0-20% CMA/CHCl3) afforded an off white solid, which was recrystallized from ethyl acetate to give tert-butyl (10S)-6-amino-10-methyl-9,10-dihydro-8H-imidazo[1′,2′:1,2]imidazo[4,5-c]quinoline-8-carboxylate (0.26 g) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[CH3:26][C:27]1[C:36](B2OC(C)(C)C(C)(C)O2)=[C:35]([CH3:46])[CH:34]=[CH:33][C:28]=1[C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[Na+].[Na+]>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>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:36]5[C:27]([CH3:26])=[C:28]([CH:33]=[CH:34][C:35]=5[CH3:46])[C:29]([O:31][CH3:32])=[O:30])[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
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: COCCOC
Product: COC(=O)c1ccc(C)c(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)c1C
Temperature: 120 °C
Yield: 30.3 %

Procedure:
N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (88 mg, 0.24 mmol) was dissolved in 1,2-dimethoxyethane (2.4 mL) in a reaction tube. Methyl 2,4-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (110 mg, 0.36 mmol), aqueous 2 M sodium carbonate (0.24 mL), and (Ph3P)4Pd (14 mg, 0.012 mmol) were added and the reaction mixture was heated at 120° C. under N2 atmosphere for 2 h in the microwave. The resulting material was cooled to room temperature, filtered, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (50-100% ethyl acetate in hexane) to yield methyl 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-2,4-dimethylbenzoate (36 mg, 30%). ESI-MS m/z calc. 494.2, found 495.5 (M+1)+. Retention time 2.18 minutes.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7](=[CH:12][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])([O-])=O.[Na].[OH:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>CN(C=O)C>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([O:19][C:4]2[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7](=[CH:12][CH:13]=2)[C:8]([O:10][CH3:11])=[O:9])[CH:21]=1
Reactant: Oc1cccnc1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C(=O)OC
Agent: [Na]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2cccnc2)cc1C(=O)OC

Procedure:
Dimethyl 4-nitrophthalate was reacted in DMF with 3-hydroxypyridine sodium salt in analogy to a process known from the literature (J. Org. Chem. Vol. 42, No. 21, 1977, 3419-3425) to give dimethyl 4-(3-pyridyloxy)phthalate. After standard working up and chromatography using hexane/EA, the diester was isolated as a yellowish oil.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[C:17]([O:19]C)=[O:18])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C(O)(=O)C>CO.O>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[C:17]([OH:19])=[O:18])[CH:12]=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C=O)cc1SCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: O=Cc1ccc(C(=O)O)c(SCc2ccccc2)c1
Yield: 95.6 %

Procedure:
To a boiling solution of 27.5 g of 3-benzylmercapto-4-carbomethoxy benzaldehye in 250 ml of methanol is added a solution of 7 g of potassium hydroxide in 24 ml of water. The reaction mixture is refluxed for 3-4 hours, then water is added to a volume of 1 liter. 10 Ml of acetic acid is added and the thus-obtained slurry is cooled, filtered, washed with water and air-dried to yield 25 g of 3-benzylmercapto-4-carboxy benzaldehyde, a yellow powder, having a melting point of 182°-190° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.[OH-].[Na+].CN(C)[CH:20]=[O:21]>O>[Cl:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9]([CH:20]=[O:21])=[CH:10][NH:11]2
Reactant: Clc1cccc2[nH]ccc12
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2cccc(Cl)c12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
During a period of five minutes 2.3 grams (0.015 mole) of phosphorus oxychloride was added dropwise to 10 mL of N,N-dimethylformamide. The solution was stirred for 30 minutes and then cooled in an ice bath. To this was added dropwise a solution of 2.0 grams (0.013 mole) of 4-chloroindole in 3 mL of N,N-dimethylformamide. Upon completion of the addition the ice bath was removed, and the reaction mixture was warmed to ambient tempeature, where it stirred for 1.5 hours. After this time the reaction mixture was warmed to 40° C., where it was stirred for 30 minutes, and then poured onto 50 grams of ice. A solution of 5.9 grams (0.146 mole) of sodium hydroxide in 20 mL of water was added during a 2-3 minute period, after which the mixture was heated to reflux and then cooled to ambient temperature. The cooled mixture was poured into 500 mL of water, stirred at ambient temperature for about 18 hours, and then filtered to collect a solid that had precipitated. The solid was washed with three portions of water and then dissolved in ethyl acetate. The ethyl acetate solution was subjected to column chromatography on silica gel with 1:1 ethyl acetate:hexane as eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 1.4 grams of 4-chloro-3-formylindole. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:20])[C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:8][C:7]=1[OH:19].[CH3:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](Cl)=[O:29])[CH2:24][CH2:23]1>C1C=CC=CC=1>[CH3:3][O:4][C:5]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:8][C:7]=1[O:19][C:28]([N:25]1[CH2:26][CH2:27][CH:22]([CH3:21])[CH2:23][CH2:24]1)=[O:29])=[O:20]
Reactant: CC1CCN(C(=O)Cl)CC1
Reactant: COC(=O)c1cc(Oc2ccccc2)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)c1cc(Oc2ccccc2)ccc1OC(=O)N1CCC(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 111.7 %

Procedure:
Sodium hydride (0.38 g, 9.93 mmol of a 60% oil dispersion) was added in portions under a nitrogen atmosphere to a solution of 2-hydroxy-5-phenoxybenzoic acid methyl ester (2.0 g, 8.19 mmol) in 30 ml of benzene. The reaction was stirred at room temperature for 30 minutes. 4-Methyl-1-piperidinecarbonyl chloride (1.46 g, 9.03 mmol) was then added and the reaction refluxed for 3.5 hours. The reaction mixture was washed with 1N HCl, dried (anhydrous MgSO4) and the solvent removed under reduced pressure to give 3.38 g of a clear oil. Purification of this oil on 300 g of silica gel (230-400 mesh) using hexane-methylene chloride as the eluent gave 2.71 g of a white crystalline solid. Recrystallization of this solid from diisopropyl ether-hexane then gave the title compound as a white crystalline solid (2.02 g, 67%), mp 67-69 C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:24]=[O:25])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]#[N:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[BH4-].[Na+].C(O)(=O)C>CO.O>[CH3:1][C:2]1[NH:3][C:4]([CH2:24][OH:25])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]#[N:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C=O)=C(C(=O)OC)C1c1ccccc1C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C1=C(C)NC(CO)=C(C(=O)OC)C1c1ccccc1C#N
Yield: 72.2 %

Procedure:
To a cold solution of dimethyl 2-methyl-4-(2-cyanophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (2.3 g) in methanol (46 ml) at -5° C. was added portionwise sodium borohydride (140.7 mg) for 10 minutes, during which the temperature was kept at -4° to -5° C. with stirring. The mixture was stirred for additional 15 minutes at -6° C. The reaction mixture was diluted with water (20 ml) and acidified to about pH 5 with 50% actic acid, and then condensed under reduced pressure to separate out crystalline product. After adding water (30 ml), the crystals were collected by filtration, washed thoroughly with water and dried. Thus obtained crystals (2.05 g) were recrystallized from methanol (15 ml) to give pure crystals of dimethyl 2-methyl-4-(2-cyanophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.67 g), mp 177° to 178° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[C:25]([NH:29][CH3:30])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([N:29]([CH3:30])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Reactant: CNC(C)(C)C
Product: CN(CCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1)C(C)(C)C

Procedure:
The product from Example 1C and tert-butyl(methyl)amine were processed as described in Example 1D to provide the titled compound. MS (DCI) m/z 333 (M+H)+;
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B(O)O)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Br[C:15]1[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:15]3[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: Cn1ncc2cc(B(O)O)ccc21
Reactant: Nc1ccc(Br)nc1
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: C1COCCO1
Product: Cn1ncc2cc(-c3ccc(N)cn3)ccc21
Temperature: 110 °C

Procedure:
In a 10-20 mL reaction vial, the 1-methyl-1H-indazol-5-ylboronic acid (250 mg, 1.34 mmol) and the 6-bromopyridin-3-amine (250 mg, 1.34 mmol) were dissolved in dioxane (7 mL) and water (1.5 mL) under argon atmosphere. The mixture was bubbled with argon for 5 min and then potassium carbonate (368 mg, 2.67 mmol) and Pd(PPh3)4 (231 mg, 0.2 mmol) were added sequentially. The resulting reaction mixture was then sealed and heated in oil bath at 110° C. for 3 h. Reaction was then partitioned between EtOAc (30 mL) and water (30 mL).The organic phase was washed with water (3×20 mL) and was concentrated. Residue was purified on silica gel column with 0-75% EtOAc/Hex to afford the title compound. LCMS-ESI+: calc'd for: C13H12N4: 225.1 (M+H+); found: 225.2 (M+H+).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C@H:10]2[N:15]([CH2:16][C:17]([OH:19])=O)[C:14](=[O:20])[C:13]([CH2:23][CH3:24])([CH2:21][CH3:22])[NH:12][CH2:11]2)[CH:6]=[C:7]([F:9])[CH:8]=1.[NH2:25][C:26]1[CH:27]=[C:28]2[C:49](=[CH:50][CH:51]=1)[CH2:48][C@:30]1([C:38]3[C:33](=[N:34][CH:35]=[CH:36][CH:37]=3)[N:32](COCC[Si](C)(C)C)[C:31]1=[O:47])[CH2:29]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[F:2][C:3]1[CH:4]=[C:5]([C@H:10]2[N:15]([CH2:16][C:17]([NH:25][C:26]3[CH:27]=[C:28]4[C:49](=[CH:50][CH:51]=3)[CH2:48][C@:30]3([C:38]5[C:33](=[N:34][CH:35]=[CH:36][CH:37]=5)[NH:32][C:31]3=[O:47])[CH2:29]4)=[O:19])[C:14](=[O:20])[C:13]([CH2:21][CH3:22])([CH2:23][CH3:24])[NH:12][CH2:11]2)[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: C[Si](C)(C)CCOCN1C(=O)[C@@]2(Cc3ccc(N)cc3C2)c2cccnc21
Reactant: CCC1(CC)NC[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCC1(CC)NC[C@@H](c2cc(F)cc(F)c2)N(CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of [(6R)-6-(3,5-difluorophenyl)-3,3-diethyl-2-oxopiperazin-1-yl]acetic acid hydrochloride (43 mg, 0.119 mmol, described in Intermediate 29), (R)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (30 mg, 0.119 mmol, described in Intermediate 9), HOBT (27 mg, 0.179 mmol), and EDC (34 mg, 0.179 mmol) in DMF (0.5 mL) was stirred at ambient temperature for 18 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were combined, basified with saturated aqueous NaHCO3, and extracted with EtOAc. The organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=560 (M+1). HRMS: m/z=560.2469; calculated m/z=560.2468 for C31H32F2N5O3.
Reaction SMILES: BrCCBr.Cl[C:6]1([F:18])[C:11](Cl)([F:12])[O:10][C:9]([F:15])([F:14])[C:8]([F:17])([F:16])[O:7]1>CN(C=O)C.[Zn]>[F:15][C:9]1([F:14])[C:8]([F:16])([F:17])[O:7][C:6]([F:18])=[C:11]([F:12])[O:10]1
Reactant: FC1(F)OC(F)(Cl)C(F)(Cl)OC1(F)F
Agent: [Zn]
Solvent: BrCCBr
Solvent: CN(C)C=O
Product: FC1=C(F)OC(F)(F)C(F)(F)O1
Yield: 45.1 %

Procedure:
A suspension of 39.2 g (0.60 mol) of zinc dust in 300 mL of dry DMF was stirred under N2 while 5 mL of 1,2-dibromoethane was added. Then a small portion of 74.0 g (0.28 mol) of dichloride 5 was added, and the mixture was stirred and heated. When an exothermic reaction started (about 75° C.), the rest of 5 was added dropwise at a rate sufficient to maintain 110°-120° C. in the pot while product was collected in a -80° C. trap. When the addition was completed, the mixture was heated to reflux to drive out the last of the product. Fractionation of the crude volatile product gave 24.5 g (45%) of pure perfluoro-2,3-dihydro-1,4-dioxin (7), bp 18°-19.5° C. IR (gas): 1845 cm-1 (w, C=C).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[F:12][C:13]([F:20])([F:19])[C:14]([NH:16][CH2:17]O)=[O:15]>OS(O)(=O)=O>[F:12][C:13]([F:20])([F:19])[C:14]([NH:16][CH2:17][C:10]1[C:2]([CH3:1])=[C:3]([C:7]([CH3:11])=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5])=[O:15]
Reactant: O=C(NCO)C(F)(F)F
Reactant: Cc1cccc(C)c1C(=O)O
Agent: O=S(=O)(O)O
Product: Cc1ccc(CNC(=O)C(F)(F)F)c(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 56519.7 %

Procedure:
To a solution of 2,6-dimethyl benzoic acid (6.8 g, 0.045 mmol) in conc. H2SO4 (100 mL), 2,2,2-trifluoro-N-(hydroxymethyl)acetamide (7.1 g, 0.049 mmol) was added and the reaction mixture was stirred at RT for 24 h. After completion of the reaction, the reaction mass was quenched in ice water and stirred for 15 minutes. The obtained solid product was filtered and dried to afford 7.0 g of the desired title product. 1H NMR (300 MHz, DMSO d6): δ 2.26 (s, 6H), 4.36 (t, J=12.3 Hz, 2H), 7.09 (m, 1H), 7.15 (m, 1H), 9.89-9.94 (m, 1H).
Reaction SMILES: [Cs+].[Cl:2][C:3]1[C:11]([O:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=[C:8]([Cl:20])[C:4]=1[C:5]([O-:7])=[O:6].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:28][N:29]1[C:33](=[O:34])[CH:32]([CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[N:31]([CH3:40])[S:30]1(=[O:42])=[O:41]>CO>[ClH:2].[Cl:2][C:3]1[C:11]([O:12][CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:10][CH:9]=[C:8]([Cl:20])[C:4]=1[C:5]([O:7][CH2:28][N:29]1[C:33](=[O:34])[CH:32]([CH2:35][CH2:36][CH:37]([CH3:38])[CH3:39])[N:31]([CH3:40])[S:30]1(=[O:41])=[O:42])=[O:6]
Reactant: CC(C)CCC1C(=O)N(CCl)S(=O)(=O)N1C
Reactant: O=C([O-])c1c(Cl)ccc(OCCN2CCCC2)c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: CC(C)CCC1C(=O)N(COC(=O)c2c(Cl)ccc(OCCN3CCCC3)c2Cl)S(=O)(=O)N1C
Product: Cl

Procedure:
To a solution of 2,6-dichloro-3-(2-pyrrolidinoethoxy)-benzoic acid cesium salt (prepared by reaction of the acid (1.045 g, 3.069 mmol) in 30 ml of methanol with Cs2CO3 (1.2 g) followed by removal of the solvent) in DMF was added 2-chloromethyl-4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (0.75 g; 1.86 mmol) at room temperature. The resulting solution was allowed to react at room temperature under nitrogen for 17 hours. The mixture was concentrated in vacuo and the residue was dissolved in 70% ethyl acetate in ether, filtered, and washed with sodium bicarbonate solution and dried over sodium sulfate. The organic solution was concentrated, the residual clear oil dissolved in 40 ml of ether and treated with ether/HCl. The salt was purified from methanol/ether to afford 2-(2,6-dichloro-3-(2-pyrrolidinoethoxy)phenylcarbonyloxymethyl)-4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide hydrochloride (Formula I: Ar=2,6-Cl2 -3-(OCH2CH2 -1-pyrrolidinyl)phenyl; R1 =H; R2 =(CH2)2CH(CH3)2 ; R3 =CH3 ; as HCl salt) a solid, m.p. 161°-162° C.