Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH:19]1([CH:23]=O)[CH2:22][CH2:21][CH2:20]1.O>C1COCC1.CN(C=O)C>[CH:19]1(/[CH:23]=[CH:9]/[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:22][CH2:21][CH2:20]1
Reactant: O=CC1CCC1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)/C=C/C1CCC1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
6.4 ml (27.3 mmol) of tert-butyl (diethoxyphosphoryl)acetate were added dropwise to a suspension, cooled to 0° C., of 1.05 g (60% in mineral oil, 26.2 mmol) of sodium hydride in a mixture of 22 ml of THF and 22 ml of DMF. After 30 min, the mixture was cooled to −10° C., and 2.0 g (crude, about 23.8 mmol) of cyclobutanecarbaldehyde were added in several portions. The reaction mixture was stirred at 0° C. for 5 h and then slowly warmed to RT overnight, subsequently added to water and extracted three times with ethyl acetate. The organic phases were combined and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 50:1). This gave 1.21 g of the target product (about 28% of theory).
Reaction SMILES: [N:1]1[C:2](=O)[NH:3][CH:4]=[C:5]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=12.O(Cl)[Cl:15].[P+3]>>[Cl:15][C:2]1[N:3]=[CH:4][C:5]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:1]=1
Reactant: O=c1nc2c(c[nH]1)CCCCCC2
Reactant: ClOCl
Agent: [P+3]
Product: Clc1ncc2c(n1)CCCCCC2

Procedure:
Crude 5,6,7,8,9,10-Hexahydrocycloocta[d]pyrimidin-2(3H)-one was heated in phosphorus (III) oxychloride (50 mL) for 1.75 h. The solvent was removed under vacuum and the residue was treated with ice water and 1M aqueous potassium carbonate solution, the aqueous layer was extracted with a mixture of diethyl ether and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 2-chloro-5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidine as a yellow solid, 1.5 g; 1H NMR (CDCl3, 300 MHz) 8.18 (s, 1H), 2.82 (m, 2H), 2.66 (m, 2H), 1.74 (m, 2H), 1.61 (m, 2H), 1.34 (m, 4H) ppm; 13C NMR (CDCl3, 75 MHz) 173.25, 158.66 (2C), 132.74, 34.28, 32.03, 30.20, 28.57, 26.02, 25.90; MS (ES) 197/199 (M+H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:14]([CH3:16])[CH3:15]>ClCCl>[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([C:5](=[O:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:19][CH:18]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CCCCCC(=O)Cl
Reactant: CC(C)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCC(=O)c1ccc(CC(C)C)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of aluminum chloride (6.67 g) in dichloromethane (70 ml) was added hexanoyl chloride (7.0 ml) at 0° C. After the mixture was stirred at 0° C. for 15 minutes, isobutylbenzene (7.9 ml) was added to the mixture. The mixture was stirred at 0° C. for 30 minutes and poured into ice water. The separated organic layer was washed with water, aqueous sodium bicarbonate and brine. The solution was dried over magnesium sulfate and evaporated to give 4'-isobutylhexanophenone (10.52 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=2)[CH:8]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:28][C:29]1[CH:30]=[C:31]([C:36]2[N:40]=[C:39]([CH:41]3[CH2:44][N:43]([C:45]([O:47][CH3:48])=[O:46])[CH2:42]3)[O:38][N:37]=2)[CH:32]=[CH:33][C:34]=1[CH3:35]>ClCCl.N1C=CC=CC=1>[CH3:35][C:34]1[CH:33]=[CH:32][C:31]([C:36]2[N:40]=[C:39]([CH:41]3[CH2:42][N:43]([C:45]([O:47][CH3:48])=[O:46])[CH2:44]3)[O:38][N:37]=2)=[CH:30][C:29]=1[NH:28][C:12]([C:9]1[N:7]2[CH:8]=[C:3]([C:2]([F:1])([F:16])[F:15])[CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14]
Reactant: O=C(O)c1cnc2ccc(C(F)(F)F)cn12
Reactant: COC(=O)N1CC(c2nc(-c3ccc(C)c(N)c3)no2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5ccc(C(F)(F)F)cn45)c3)no2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirring suspension of 6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylic acid (24a) (50 mg, 0.217 mmol) in anhydrous dichloromethane (2 mL) at 0° C. under Argon was added dropwise oxalyl chloride (19 μL, 0.228 mmol). Then, a drop of anhydrous DMF was added and the reaction mixture was stirred at room temperature for 1.5 hours. The solvent was concentrated and the crude solid was added portion-wise to a stirring solution of methyl 3-(3-(3-amino-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (31) (47 mg, 0.163 mmol) in anhydrous pyridine (1 mL) at 0° C. The reaction was stirred at room temperature under Argon for 10 minutes and quenched with water. The crude product was purified by preparative HPLC to yield methyl 3-(3-(4-methyl-3-(6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxamido)phenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F52). 1H NMR (400 MHz, d6-DMSO) δ 10.27 (s, 1H), 9.90-9.85 (m, 1H), 8.72 (s, 1H), 8.08 (d, J=1.6 Hz, 1H), 8.02-7.99 (m, 1H), 7.86 (dd, J=2.0, 8.0 Hz, 1H), 7.79 (dd, J=2.0, 9.2 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 4.37-4.19 (m, 5H), 3.59 (s, 3H), 2.37 (s, 3H). MS m/z 501.43 (M+1)+.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([N:16]=[C:17]=[S:18])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[C:19]([NH:22][NH2:23])(=[O:21])[CH3:20].CO>O1CCCC1>[C:19]([NH:22][NH:23][C:17]([NH:16][C:12]1[CH:13]=[CH:14][C:15]2[N:3]([CH2:1][CH3:2])[C:4]3[C:9]([C:10]=2[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[S:18])(=[O:21])[CH3:20]
Reactant: CC(=O)NN
Reactant: CCn1c2ccccc2c2cc(N=C=S)ccc21
Solvent: CO
Solvent: C1CCOC1
Product: CCn1c2ccccc2c2cc(NC(=S)NNC(C)=O)ccc21

Procedure:
3.8 g of 9-ethyl-3-isothiocyanatocarbazole was reacted with 1.1 g of acetylhydrazine in 30 ml of tetrahydrofuran at 60° C. for 2 hours. Then, 10 ml of methanol was added thereto and crystallization was conducted while cooling with ice. Crystals thus precipitated were collected by filtration, and recrystallized from CHCl3 /CH3OH (70 ml/200 ml) to obtain 2.4 g of the desired end compound. m.p. 197°-199° C.
Reaction SMILES: CC(C1C=C2CC[CH:12]3[C:17]([C:19]([OH:21])=O)(C)[CH2:16][CH2:15][CH2:14][C:13]3(C)C2CC1)C.[C:23](OCC1C=CC=CC=1)(=[O:30])[C:24]1C=CC=CC=1.C(OC(C)C)(=[O:53])CCCCCCCCCCCCC>>[O:21]=[CH:19][C:17]1[CH:16]=[CH:15][C:14]([OH:53])=[C:13]([O:30][CH2:23][CH3:24])[CH:12]=1
Reactant: O=C(OCc1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCC(=O)OC(C)C
Reactant: CC(C)C1C=C2CCC3C(C)(C(=O)O)CCCC3(C)C2CC1
Product: CCOc1cc(C=O)ccc1O

Procedure:
The foregoing formula may require a solubilizing agent, e.g., the methyl ester of dihydroabietic acid (commerical name: HERCOLYN D®), benzyl benzoate, isopropyl myristate and/or C12 -C14 isoparaffin hydrocarbons.
Reaction SMILES: Cl[C:2]1[C:3]([C:27]2[CH:32]=[CH:31][C:30](Cl)=[CH:29][CH:28]=2)=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[C:5]2[N:6]([C:8](=[O:19])[N:9]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:10]=2)[N:7]=1.C[Si]([O:38][Si](C)(C)C)(C)C.[K].[ClH:44]>C1COCC1>[Cl:44][C:30]1[CH:29]=[CH:28][C:27]([C:3]2[C:2](=[O:38])[NH:7][N:6]3[C:8](=[O:19])[N:9]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:17])[CH3:18])[N:10]=[C:5]3[C:4]=2[C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)=[CH:32][CH:31]=1
Reactant: C[Si](C)(C)O[Si](C)(C)C
Reactant: Cl
Reactant: C[Si](C)(C)CCOCn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c(Cl)nn2c1=O
Agent: [K]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c(=O)[nH]n2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To the solution of 6-chloro-7,8-bis(4-chlorophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (0.48 g, 0.92 mmol) in THF (20 ml) was added potassium trimethylsilyloxide (TMSOK) (0.25 g, 1.95 mmol). The solution was heated to reflux. After 0.5 h, the solution was cooled to RT and 1N HCl solution was added until the reaction was acidic. The resulting solution was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using an automated system to give the title compound, 7,8-bis(4-chlorophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazine-3,6(2H,5H)-dione, (260 mg, 56%) as a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:19](=[S:21])[NH2:20])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(C)(C)C.[Br:23][CH2:24][C:25](=O)[CH2:26][CH3:27].C(OCC)C>CC#N>[BrH:23].[CH2:26]([C:25]1[N:20]=[C:19]([C@@H:8]([NH2:7])[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)[S:21][CH:24]=1)[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(N)=S
Reactant: CCC(=O)CBr
Solvent: CCOCC
Solvent: CC#N
Product: Br
Product: CCc1csc([C@@H](N)Cc2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C

Procedure:
A mixture of [2-(4-nitrophenyl)-1-(S)-thiocarbamoylethyl]-carbamic acid tert-butyl ester, 2, (10 g, 30.7 mmol) and 1-bromo-2-butanone (90%, 3.8 mL, 33.8 mmol) in CH3CN (500 mL) is refluxed for 18 hours. The reaction mixture is cooled to room temperature and diethyl ether is added to the solution and the precipitate which forms is removed by filtration to afford 7.47 g of the desired product. ESI+ MS 278 (M+1).
Reaction SMILES: [C:1]([Si:5]([O:8][C@@H:9]1[C@H:18]2[C@@:13]([CH3:26])([C@@H:14]([C@H:19]([CH3:25])[CH2:20][CH:21]=[C:22](Br)Br)[CH2:15][CH2:16][CH2:17]2)[CH2:12][CH2:11][CH2:10]1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[CH3:32][C:33]([CH3:35])=[O:34].[C-]#[C-]>C1COCC1>[C:1]([Si:5]([CH3:7])([CH3:6])[O:8][C@H:9]1[CH2:10][CH2:11][CH2:12][C@@:13]2([CH3:26])[C@H:18]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[C@H:19]([CH3:25])[CH2:20][C:21]#[C:22][C:33]([CH3:35])([OH:34])[CH3:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](CC=C(Br)Br)[C@H]1CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Reactant: CC(C)=O
Agent: [C-]#[C-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](CC#CC(C)(C)O)[C@H]1CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Yield: 79.1 %

Procedure:
3.05 g (6.00 mmol) of tert-butyl-[(1S,4aR,5R,8aR)-5-((R)-4,4-dibromo-1-methyl-but-3-enyl)-4a-methyl-decahydro-naphthalen-1-yloxy]-dimethyl-silane was dissolved in 35 ml of abs. THF and cooled down to -78°. 11.6 ml of nBuLi (1.55M, hexane) was slowly added and the temperature maintained for 1 h. 2.15 ml (29.3 mmol) of acetone, dissolved in 5 ml of abs. THF, was then added to the resultant acetylide-solution and allowed to react for 30 minutes. The reaction was quenched by pouring onto crushed ice/NH4Cl, extracted twice with ether, washed with water and brine, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=9/1) yielded 1.93 g of the title compound as colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH:26]1[CH2:31][CH2:30][CH:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1)(=O)=O.CN(C=O)C>C(OCC)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH:10]=2)[O:3]1
Reactant: CC(C)(C)OC(=O)C1CCC(OS(C)(=O)=O)CC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 90 °C
Reaction time: 22 h

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (325 mg, 1.67 mmol), cesium carbonate (600 mg, 1.84 mmol), and tert-butyl 4-[(methylsulfonyl)oxy]cyclohexanecarboxylate (513 mg, 1.84 mmol) followed by DMF (5.6 mL) were added to an oven-dried flask. The reaction mixture was stirred at 90° C. for 22 hours then cooled to room temperature, diluted with diethyl ether, washed with water (3×50 mL), and then brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]cyclohexanecarboxylate (mixture of cis and trans). 1H NMR (500 MHz, CDCl3) δ 7.99 (s, 1H), 7.86 (s, 1H), 2.98 (s, 1H), 2.24-1.85 (m, 5H), 1.75-1.43 (m, 4H), 1.41 (s, 9H), 1.29 (s, 12H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:5]2=[N:6][CH:7]=1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C>COCCOC.CCCCCC.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>[Cl:21][C:22]1[N:23]=[C:24]([C:2]2[CH:3]=[C:4]3[C:10]([CH3:11])=[N:9][N:8]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)[C:5]3=[N:6][CH:7]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccc(Cn2nc(C)c3cc(Br)cnc32)cc1
Reactant: CC1(C)OB(c2cccc(Cl)n2)OC1(C)C
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: [Cs+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(Cn2nc(C)c3cc(-c4cccc(Cl)n4)cnc32)cc1
Temperature: 100 °C
Yield: 39.3 %

Procedure:
To a stirred solution of 5-bromo-1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine (7) (139 mg, 0.418 mmol) in 1,2-dimethoxyethane (10 mL) was added 2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (99) (100 mg, 0.418 mmol) and Cs2CO3 (32 mg, 0.104 mmol). The resulting reaction mixture was degassed, purged with N2 for 15 min, Pd(PPh3)4 (19 mg, 0.0167 mmol) was added and the mixture purged again under nitrogen for another 15 min. The reaction mass was heated at 100° C. in a sealed tube for 12 h. After completion of the reaction the reaction mass was partitioned between ethyl acetate and water and the organic layer was separated and extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 and the solvent completely distilled off to get the crude product. The crude material was passed through 100-200 mesh silica gel eluting the pure compound at 50% ethyl acetate in hexane to yield off white colored solid compound 5-(6-chloropyridin-2-yl)-1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine 100 (60 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([P:8](=[O:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[N:16]=[C:15]([Cl:20])[N:14]=1>CN(C)C=O.C(N(C(C)C)CC)(C)C>[Cl:12][C:13]1[N:14]=[C:15]([Cl:20])[N:16]=[C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([P:8]([CH3:9])([CH3:10])=[O:11])=[CH:6][CH:7]=2)[N:18]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CP(C)(=O)c1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CP(C)(=O)c1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Temperature: 0 °C

Procedure:
A suspension of 4-amino-dimethylphenylphosphine oxide (3.7 g, 2.2 mmol) in 15 mL of N,N-Dimethylformamide and 3.6 mL of Diisopropylethylamine is cooled to 0° C. 2,4,6-trichloro-1,3,5-triazine (2.6 mmol) is added in four portions over 5 minutes. The reaction mixture is warmed up to room temperature and stirred until formation of the desired compound. The reaction mixture is filtered and purified by prep-HPLC.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[O:11][CH2:10][C:9]([CH3:13])([CH3:12])[O:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[CH:30][C:31]([NH2:34])=[N:32][CH:33]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:9]1([CH3:13])[O:8][C:6]2[N:7]=[C:2]([C:28]3[CH:29]=[CH:30][C:31]([NH2:34])=[N:32][CH:33]=3)[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:5]=2[O:11][CH2:10]1
Reactant: CC1(C)COc2c(nc(Cl)nc2N2CCOCC2)O1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC1(C)COc2c(nc(-c3ccc(N)nc3)nc2N2CCOCC2)O1
Temperature: 120 °C
Yield: 51.8 %

Procedure:
A microwave vial was charged with 2-chloro-7,7-dimethyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine from Example 104 (50 mg, 0.18 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (58 mg, 0.26 mmol), Pd(PPh3)2Cl2 (12 mg, 0.02 mmol) and sodium carbonate (0.5 mL, 0.5 mmol, 1M aqueous solution) in acetonitrile (1.5 mL) then evacuated and back filled with nitrogen before being heated at 120° C. for 30 minutes using microwave irradiation. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with methanol and the product eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient of acetonitrile 5-98%) affording 111 as a white solid (32 mg, 53%). LCMS: RT=2.73 min, [M+H]+=344. 1H NMR (400 MHz, CDCl3): δ 9.01 (1H, d, J=2.1 Hz), 8.33 (1H, dd, J=2.1, 8.5 Hz), 6.50 (1H, d, J=8.5 Hz), 4.61 (2H, broad s), 3.89 (2H, s), 3.86-3.77 (8H, m), 1.43 (6H, s)
Reaction SMILES: [CH2:1]([C:3]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]([OH:9])=[N:7][C:6](=[O:10])[N:5]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16])[C:4]1=[O:19])[CH3:2].O>O1CCOCC1.Cl>[C:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:5]1[C:4](=[O:19])[C:3]([CH2:1][CH3:2])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:8]([OH:9])=[N:7][C:6]1=[O:10])([OH:17])=[O:16]
Reactant: CCC1(c2ccccc2)C(=O)N(CCCCC(=O)OC)C(=O)N=C1O
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCC1(c2ccccc2)C(=O)N(CCCCC(=O)O)C(=O)N=C1O
Temperature: 25 °C

Procedure:
The 5-ethyl-6-hydroxy-3-(4-methoxycarbonylbutyl)-5-phenyl2,4(3H,5H)-pyrimidinedione ester (54.0 g, 0.156 mole) of step 1 in dioxane (500 mL), concentrated hydrochloric acid (55 mL), and water (55 mL) was heated at reflux for 4 hrs and at room temperature ovenight. The dioxane was removed under reduced pressure, and saturated sodium chloride solution (250 mL) and dichloromethane (400 mL) were added to the residue. The organic layer was separated, and the aqueous solution was extracted with dichloromethane (3×150 mL). The combined organic solutions were washed with saturated sodium chloride solution (200 mL), dried over anhydrous MgSO4, filtered, and the solvent removed. To the residue was added diethyl ether, and the mixture was placed in a freezer at -16° C. over the weekend, and then filtered.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]1[C:30]2([CH2:36][CH2:35][NH:34][CH2:33][CH2:32][O:31]2)[CH2:29][CH2:28][N:27]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:26]1.[CH3:44][C:45]1[S:46][CH:47]=[C:48]([C:50](O)=[O:51])[N:49]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:44][C:45]1[S:46][CH:47]=[C:48]([C:50]([N:34]2[CH2:35][CH2:36][C:30]3([CH2:29][CH2:28][N:27]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:26][CH2:25]3)[O:31][CH2:32][CH2:33]2)=[O:51])[N:49]=1
Reactant: Cc1nc(C(=O)O)cs1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCCO2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)CC2)cs1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
HATU (0.322 g) was added in one portion to a solution at 0° C. of tert-butyl 7-oxa-3,10-diazaspiro[5.6]dodecane-3-carboxylate (example 89, step e) (0.176 g) and 2-methylthiazole-4-carboxylic acid (0.093 g) and triethylamine (0.36 mL) in DMF (10 mL). The mixture was then stirred at 20° C. for 1 hour. The reaction mixture was partitioned between ethyl acetate and brine. The organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography eluting with ethyl acetate. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 210 mg.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[C@@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:6][O:5][C:4]1=[O:16].Cl.[N:18]([O-])=O.[Na+]>O>[ClH:1].[CH3:2][N:3]1[C@@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][NH2:18])=[CH:11][CH:10]=2)[CH2:6][O:5][C:4]1=[O:16]
Reactant: CN1C(=O)OC[C@@H]1Cc1ccc(N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CN1C(=O)OC[C@@H]1Cc1ccc(NN)cc1
Reaction time: 0.5 h

Procedure:
A solution of the product from step (b) (4.1 g) in water (24 ml) was cooled to -5° C. and c.HCl (40 ml) added. A solution of sodium nitrite (1.2 g) in water (12 ml) was then added and stirring continued for 0.5 hour. The resulting solution was added dropwise at -5° C. to a stirred solution of stannous chloride dihydrate (18.8 g) in c.HCl (34 ml). The resulting mixture was stirred at 0° C. for 2.5 hours, then evaporated in vacuo. The residue was taken up in water, brought to pH 2.5 using 10N aqu. NaOH and filtered. The filtrate was evaporated in vacuo and the residue triturated with ethanol and filtered. The filtrate was evaporated in vacuo to give the desired product as a froth.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)[CH:2]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[S:46][CH:47]([C:51](O)=[O:52])[C:48](O)=[O:49])([CH3:39])[CH3:38]>C(Cl)Cl>[OH:52][C:51]1[CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:10][CH:11]=2)[O:17][C:48](=[O:49])[C:47]=1[S:46][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[CH:37]([CH3:39])[CH3:38]
Reactant: CC(=O)c1ccc(OCc2cccnc2)cc1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2ccc(OCc3cccnc3)cc2)oc1=O

Procedure:
The title compound was prepared by Method A using 4'-(pyridin-3-ylmethoxy)acetophenone (1.09 g, 4.83 mmol), trimethylsilyl triflate (1.12 mL, 5.79 mmol), triethylamine (1.34 mL, 9.66 mmol), methylene chloride (17 mL), and diethyl ester of [(2-isopropylphenyl)thio]-propanedioic acid (1.00 g, 3.22 mmol) m.p. 225° C.; ; 1H NMR (400 MHz, DMSO-d6) δ 1.23 (d, 6H), 3.41 (m, 1H), 5.26 (s, 2H), 6.78 (s, 1H), 6.90 (d, 1H), 7.08 (dt, 2H), 7.21 (d, 2H), 7.29 (d, 1H), 7.45 (dd, 1H), 7.82 (d, 2H), 7.91 (d, 1H), 8.56 (d, 1H), 8.71 (s, 1H).