Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH:12]([C:18]#[N:19])C(OCC)=O)[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.[Li+].[Cl-].O>CS(C)=O>[C:18]([CH2:12][C:2]1([CH3:1])[CH2:3][C:4]([CH3:11])([CH3:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7]1)#[N:19]
Reactant: CCOC(=O)C(C#N)C1(C)CC(C)(C)CC(C)(C)C1
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)CC(C)(C)CC(C)(CC#N)C1
Temperature: 155 °C
Yield: 92.3 %

Procedure:
The mixture of ethyl (1,3,3,5,5-pentamethylcyclohexyl)cyanoacetate (17) (1g, 3,7 mmol), LiCl (0.05 g) and water (0.15 ml) in DMSO (2.5ml) was heated at 150-160° C. for 4 h. Solution was poured into water (70 ml) and extracted with ether (4*20 ml). Ether was washed with saline (2*50 ml), dried over Na2SO4, filtered and evaporated. Crude product was purified on silica gel column, eluting with a petroleum ether-ethyl acetate mixture (20:1) to give 0.66 g (94%) of 18 as an oil.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.FC1C=C(CN[C@]23CC[C@@H](C(C)=C)[C@@H]2[C@@H]2[C@@](C)(CC3)[C@@]3(C)[C@@H]([C@]4(C)[C@@H](CC3)C(C)(C)C(C3C=CC(C(O)=O)=CC=3)=CC4)CC2)C=CN=1.[F:88][C:89]1[CH:90]=[CH:91][C:92]([CH:95]=O)=[N:93][CH:94]=1>>[F:88][C:89]1[CH:90]=[CH:91][C:92]([CH2:95][NH:1][C@:2]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)=[N:93][CH:94]=1
Reactant: O=Cc1ccc(F)cn1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NCc3ccnc(F)c3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCc3ccc(F)cn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 47 %

Procedure:
The title compound was prepared in 47% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-fluoropyridin-4-yl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 5-fluoro-2-formylpyridine was used instead of 2-fluoropyridine-4-carboxaldehyde in Step 1. LCMS: m/e 639.5 (M+H)+, 3.33 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=8.46 (d, J=2.7 Hz, 1H), 7.93 (d, J=8.2 Hz, 2H), 7.68 (dt, J=2.7, 8.2 Hz, 1H), 7.53 (dd, J=4.1, 8.7 Hz, 1H), 7.21 (d, J=8.5 Hz, 2H), 5.31 (dd, J=1.7, 6.3 Hz, 1H), 4.83 (s, 1H), 4.74 (s, 1H), 4.49 (d, J=15.3 Hz, 1H), 4.32 (d, J=15.0 Hz, 1H), 2.78 (dt, J=5.3, 10.9 Hz, 1H), 2.22-2.06 (m, 5H), 1.96 (dt, J=3.4, 12.2 Hz, 1H), 1.89-1.82 (m, 1H), 1.80 (d, J=10.7 Hz, 2H), 1.76 (s, 3H), 1.74-1.66 (m, 2H), 1.64-1.54 (m, 4H), 1.53-1.47 (m, 2H), 1.46-1.42 (m, 1H), 1.41-1.37 (m, 1H), 1.33 (s, 3H), 1.29 (dd, J=3.8, 9.9 Hz, 1H), 1.24 (dd, J=4.1, 13.0 Hz, 1H), 1.13 (s, 3H), 1.07 (s, 3H), 0.97 (s, 3H), 0.95 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[C:11]([OH:23])[C:10]=1[C:24](=[O:26])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[C:11]([O:23][C:34]2[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=2)[C:10]=1[C:24](=[O:26])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1c(O)cc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1c(OCc2ccccc2)cc(OCc2ccccc2)cc1Oc1ccc([N+](=O)[O-])cc1
Temperature: 110 °C
Yield: 73 %

Procedure:
A stirred suspension of 1-[2,4-bis(benzyloxy)-6-hydroxyphenyl]ethanone (Bulletin of the Chemical Society of Japan (1985), 58(1), 136-41) (5.2 g, 15 mmol), potassium carbonate (3.1 g, 22 mmol) and 1-fluoro-4-nitrobenzene (2.1 g, 15 mmol) in DMF (10 mL) was heated at 110° C. for 2 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and thoroughly washed with brine (4×50 mL). The organic phase was dried over Na2SO4 and then evaporated to dryness. The crude was chromatographed on a small pad of silica gel eluting with hexane/ethyl acetate 5/1, to provide the title compound (5 g, 73% yield).
Reaction SMILES: [OH:1][CH:2]([C:7]([O:20][CH2:21][C:22](=[O:32])[N:23]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5]C)=[O:4].[OH-].[Na+].O>O1CCOCC1>[OH:1][CH:2]([C:7]([O:20][CH2:21][C:22](=[O:32])[N:23]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4]
Reactant: CCCCN(CCCC)C(=O)COC(c1ccccc1)(c1ccccc1)C(O)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCCN(CCCC)C(=O)COC(c1ccccc1)(c1ccccc1)C(O)C(=O)O
Yield: 80 %

Procedure:
1.42 g of methyl 2-hydroxy-3-(N,N-dibutylcarbamoylmethoxy)-3,3-diphenylpropionate were dissolved in 10 ml of dioxane and 4.8 ml of 1N sodium hydroxide solution and stirred at room temperature for 3 hours. Water was then added to the mixture, and the aqueous phase was extracted with ether. The aqueous phase was acidified with hydrochloric acid and extracted with ethyl acetate, and the organic phase was dried over magnesium sulfate. After removal of the solvent by distillation, 1.1 g of oil were isolated and were immediately employed further.
Reaction SMILES: C(C#N)[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4].[OH-:18].[K+].[CH2:20]([OH:22])[CH3:21]>O>[CH3:4][C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:2][CH2:21][C:20]([OH:18])=[O:22]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCC#N
Reactant: CCO
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: CC(C)=CCCC(C)=CCCC(C)=CCC(=O)O
Reaction time: 5 h

Procedure:
A mixture of 469 g (2.02 moles) farnesyl cyanide, 287 g potassium hydroxide, 2,500 ml ethanol and 340 ml water were heated under reflux. After 5 hours, the ethanol was evaporated and the residue poured into 10 liters of water. The aqueous solution so obtained was twice extracted with 1 liter diethyl ether, the extracts being discarded, and thereafter acidified with 20% sulfuric acid. Then, the free acid was extracted with diethyl ether. The etheric solution was again washed with water and dried with sodium sulfate. After evaporation of the ether, 419 g (83% of the theoretical) of homofarnesic acid were obtained as a yellow oil.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][NH:24][CH2:25]2>CN(C=O)C>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][N:24]([C:11]1[CH:12]=[C:13]3[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=1[F:15])[CH2:25]2
Reactant: Fc1cccc2c1CNC2
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Solvent: CN(C)C=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3Cc4cccc(F)c4C3)c(F)cc2c1=O
Temperature: 110 °C
Yield: 43.4 %

Procedure:
A mixture of 136 mg of 1-cyclopropyl-6,7-difluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 206 mg of 4-fluoroisoindoline, and 1.5 ml of anhydrous DMF was heated at 110° C. for 1.5 hours while stirring. The resulting reaction mixture was evaporated under reduced pressure to dryness. 20 ml of chloroform and 10 ml of 5% acetic acid were added to the residue thus obtained, and the mixture was stirred. The deposited crystals were collected by filtration and washed with water and then ethanol. The chloroform layer was separated, washed with water, dried over anhydrous sodium sulfate, and condensed. The residue was crystallized by the addition of hot ethanol. After cooling the mixture, the crystals were collected by filtration. These crystals, combined with the crystals obtained above, were recrystallized from a mixed solvent of chloroform, methanol, and ethanol to obtain 85 mg of the target compound.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:22]([O:24]C4C=CC=CC=4)=O)[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([Cl:31])[CH:18]=4)[C:13]3=[O:32])=[N:9]2)=[CH:4][CH:3]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>C(#N)C.C(Cl)Cl.C(OCC)(=O)C>[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([C:22]([O:21][CH:20]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([Cl:31])[CH:18]=3)[C:13](=[O:32])[N:12]2[C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[N:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=2)=[O:24])[CH2:36][CH2:35]1
Reactant: O=C(Oc1ccccc1)OC1c2cc(Cl)ccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Reactant: CN1CCNCC1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN1CCN(C(=O)OC2c3cc(Cl)ccc3C(=O)N2c2ccc3ccc(Cl)nc3n2)CC1
Temperature: 20 °C
Reaction time: 24 h
Yield: 59.2 %

Procedure:
The procedure of Example 11 is followed but starting with 2-(7-chloro-1,8-naphthyridin-2-yl)-5-chloro-3-phenoxycarbonyloxy-isoindolin-1-one (1.25 g.) and 4-methylpiperazine (1.07 g.) in acetonitrile (33 cc.) and stirring for 24 hours at a temperature of about 20° C. From the reaction mixture, the resulting precipitate is filtered off and washed successively with acetonitrile (6 cc.) and diethyl ether (6 cc.). The product obtained (0.93 g.) is dissolved in methylene chloride (35 cc.), and the solution passed through a column of silica gel (10 g.). Elution is carried out with methylene chloride (16 × 20 cc.); the corresponding eluates are discarded. Elution is the carried out with ethyl acetate (5 × 20 cc.); the corresponding eluates are combined and concentrated under reduced pressure. A crystalline residue (0.9 g.) is obtained and is suspended in ethyl acetate (20 cc.). The crystals are filtered off and dried to yield 3-(4methylpiperazin-1-yl)carbonyloxy-5-chloro- 2-(7-chloro-1,8-naphthyridin-2-yl)isoindolin-1-one (0.75 g.) melting at 255° C.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][N:17]=1)[C:12]([OH:14])=O.ClC(OCC(C)C)=O.[CH2:26]([SH:28])[CH3:27]>ClCCl.O>[Br:8][C:9]1[CH:10]=[C:11]([C:12](=[O:14])[S:28][CH2:26][CH3:27])[CH:15]=[CH:16][N:17]=1
Reactant: CCS
Reactant: O=C(O)c1ccnc(Br)c1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCSC(=O)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.9 %

Procedure:
Triethylamine (3.0 g, 29.7 mmol) was added to a suspension of 2-bromo-isonicotinic acid (5.0 g, 24.8 mmol) in anhydrous dichloromethane (50 mL). The mixture was stirred at room temperature for 10 minutes, cooled to 0° C. and isobutyl chloroformate (3.6 g, 26.0 mmol) was added dropwise. The reaction mixture was then stirred at 0° C. for 30 minutes, ethanethiol (1.6 g, 25.99 mmol) was then added dropwise and the stirring was continued for an additional 2 h at 0° C. The reaction mixture was diluted with dichloromethane (100 mL) and water (100 mL). The organic layer was separated, washed with water, dried over is sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography using 15% ethyl acetate in hexane to afford the title compound (5.0 g, 80%).
Reaction SMILES: I[C:2]1[C:9](=[O:10])[N:5]2[CH2:6][CH2:7][CH2:8][N:4]2[C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=1.C([Mg]Cl)(C)C.[Cl:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=[O:28]>C1COCC1>[Cl:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]([OH:28])[C:2]1[C:9](=[O:10])[N:5]2[CH2:6][CH2:7][CH2:8][N:4]2[C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=1
Reactant: CSc1nccc(-c2c(I)c(=O)n3n2CCC3)n1
Reactant: O=Cc1ccccc1Cl
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CSc1nccc(-c2c(C(O)c3ccccc3Cl)c(=O)n3n2CCC3)n1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
To a cold (−40° C.) suspension of 2-iodo-3-(2-methylsulfanyl-pyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazol-1-one, 21, (0.40 g, 1.07 mmol) in THF (3 mL) is added dropwise isopropyl-magnesium chloride (0.59 mL of a 2M solution in THF, 1.18 mmol). After stirring for 30 min at −40° C., a solution of 2-chlorobenzaldehyde (0.16 mL, 1.40 mmol) is added dropwise. The reaction mixture is allowed to warm to 0° C. over 1 h period. The mixture is quenched by pouring into aqueous saturated NH4Cl. The aqueous phase is extracted three times with EtOAc and the combined organic phases are dried (MgSO4), filtered and concentrated in vacuo. The crude residue is purified over silica (10% MeOH/chloroform) to afford 240 mg (58% yield) of desired product. 1H NMR (300 MHz, CDCl3) δ 8.56 (d, J=5.1 Hz, 1H), 7.78 (dd, J=7.2, 1.8 Hz, 1H), 7.34-7.18 (m, 2H), 7.01 (d, J=5.1 Hz, 1H), 6.21 (s, 1H), 4.20-4.01 (m, 5H), 2.80-2.70 (m, 2H), 2.58 (s, 3H); ESI+ MS: m/z (rel intensity) 371.1 (100, M++H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]([CH3:24])[CH2:19][O:20]C(=O)C)[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:25]2[CH2:28][CH2:27][CH2:26]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].ClCCl>C(O)C.O>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][C@@H:18]([CH3:24])[CH2:19][OH:20])[CH2:15][CH2:16]2)[CH:8]=[C:7]([CH:25]2[CH2:28][CH2:27][CH2:26]2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)OC[C@H](C)CN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: C[C@@H](CO)CN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Temperature: 65 °C
Yield: 81.9 %

Procedure:
5.81 g of crude (R)-acetic acid 3-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-2-methyl-propyl ester (asserted 14.1 mmol)) were stirred in 26.6 ml of ethanol. A solution of 2.83 g of sodium hydroxide in 6 ml of water was added and the reaction mixture was heated at 60-70° C. for 5 h. After cooling to room temperature, 50 ml of water and 50 ml of dichloromethane were added. The dichloromethane layer was separated and the aqueous was extracted with a further portion of dichloromethane. The combined dichloromethane extracts were washed with water, dried over magnesium sulfate, filtered and evaporated under vacuum to give an orange oil (4.0 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=C4C=C(B5OC(C)(C)C(C)(C)O5)C=CN4[C:35]=3[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1.O1[CH2:55][CH2:54]OCC1.[OH-].[Na+].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:42])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:44]4[CH:49]=[C:48]([C:55]5[CH:54]=[CH:10][CH:9]=[CH:8][N:7]=5)[CH:47]=[CH:46][N:45]4[C:35]=3[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(B5OC(C)(C)C(C)(C)O5)ccn4c3-c3ccccc3)cc2)CCC1
Reactant: Brc1ccccn1
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(-c5ccccn5)ccn4c3-c3ccccc3)cc2)CCC1
Temperature: 140 °C
Yield: 54 %

Procedure:
To a solution of (1-{4-[3-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester [prepared in a manner analogous to that described in Int 11-0; 100% yield assumed] (0.29 mmol) in DMF (3 mL) was added 2-bromopyridine (0.034 mL, 0.32 mmol, 1.1 equiv) and dioxane (1.2 mL). The resulting solution was placed under an argon atmosphere, then, [1,1-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) CH2Cl2 complex (24 mg, 0.03 mmol, 10 mol %) and an aqueous 1 N NaOH solution (0.9 mL, 1.84 mmol, 6.3 equiv) were added. The resulting mixture was heated at 140° C. for 1 h in a microwave apparatus. The resulting mixture was added to water (15 mL). The resulting mixture was extracted with EtOAc (3×25 mL), dried (Na2SO4 anh), and concentrated under reduced pressure. The remaining material was purified using MPLC (Biotage Isolera; 10 g SNAP cartridge: 100% hexane for 2 min., gradient to 70% hexane/30% EtOAc over 1 min., 70% hexane/30% EtOAc for 3 min., gradient to 50% hexane/50% EtOAc over 1.5 min., 50% hexane/50% EtOAc for 2.5 min., gradient to 100% EtOAc over 1 min., 100% EtOAc for 9.6 min,) to give {1-[4-(3-phenyl-7-pyridin-2-yl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (85 mg, 54% two steps):
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:3]([OH:26])[CH2:4][C@@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.FC(F)(F)C(O)=O.[CH3:41][C@@H:42]([CH2:65][CH3:66])[C@H:43]([N:47]1[CH2:51][CH2:50][N:49]([CH2:52][C:53]2[N:54]=[C:55]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=3)[S:56][CH:57]=2)[C:48]1=[O:64])[C:44](O)=[O:45].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[CH2:6]([C@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][C@H:3]([OH:26])[C@@H:2]([NH:1][C:44](=[O:45])[C@@H:43]([N:47]1[CH2:51][CH2:50][N:49]([CH2:52][C:53]2[N:54]=[C:55]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=3)[S:56][CH:57]=2)[C:48]1=[O:64])[CH:42]([CH3:41])[CH2:65][CH3:66])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2csc(-c3ccccn3)n2)C1=O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCC(C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CCN(Cc2csc(-c3ccccn3)n2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.7 %

Procedure:
A solution containing the product from Example 3D (0.025 g, 0.055 mmol) in DMF (0.5 mL) was treated with the product from Example 3L (0.021 g, 0.056 mmol), EDAC (0.020 g, 0.104 mmol), HOBT (0.015 g, 0.111 mmol), and NMM (0.020 mL, 0.182 mmol) at 0° C., stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and water. The organic phase was washed with 10% citric acid, diluted sodium bicarbonate, and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column, eluting with 5-100% acetonitrile in water (0.1% TFA) to give the title compound (0.028 g, 63% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.79 (m, 15 H), 0.95 (m, 1 H), 1.29 (m, 1 H), 1.49 (m, 2 H), 1.80 (m, 1 H), 2.68 (m, 4 H), 3.03 (m, 1 H), 3.17(m, 2 H), 3.55 (s, 3 H), 3.63 (m, 3 H), 3.94 (d, J=11.03 Hz, 2 H), 4.12 (m, 2 H), 4.47 (m, 2 H), 6.62 (d, J=9.93 Hz, 1 H), 7.07 (m, 10 H), 7.25 (d, J=9.56 Hz, 1 H), 7.48 (m, 1 H), 7.57 (s, 1 H), 7.75 (d, J=8.46 Hz, 1 H), 7.93 (m, 1 H), 8.10 (d, J=8.09 Hz, 1 H), 8.62 (d, J=4.04 Hz, 1 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[O:8])=[CH:3][CH:2]=1.[Na+].II.[CH2:21]([C:24](=[CH2:28])[C:25]([OH:27])=[O:26])[CH2:22][CH3:23].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.ClCCl>[CH2:21](/[C:24](=[CH:28]\[S:15]([C:12]1[CH:11]=[CH:10][C:9]([C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[O:8])=[CH:14][CH:13]=1)(=[O:17])=[O:16])/[C:25]([OH:27])=[O:26])[CH2:22][CH3:23]
Reactant: C=C(CCC)C(=O)O
Reactant: O=C(c1ccncc1)c1ccc(S(=O)[O-])cc1
Agent: II
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCC/C(=C\S(=O)(=O)c1ccc(C(=O)c2ccncc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
Sodium 4-(pyridine-4-carbonyl)benzenesulfinate (3.33 g, 14.04 mmol) was dissolved in water (60 ml). This solution was shaken with iodine (3.56 g, 34.29 mmol) in dishloromethane (40 ml). The dichloromethane layer turned from deep pink to orange. The dishloromethane layer was dried over magnesium sulfate and filtered into a flask containing 2-propylacrylic acid (0.8 g, 7.02 mmol). The solution was stirred overnight at room temperature and then cooled to 0° C. Triethylamine (4.0 ml, 28.08 mmol) was added and the solution was allowed to warm to room temperature over 2 hours. The mixture was acidified to pH 4 by addition of 10% citric acid. The layers were separated and the product was extracted with 2M sodium hydroxide (3×50 ml). The combined aqueous phase was washed with ethyl acetate (50 ml), the acidified to pH 4 with citric acid. The product was extracted into ethyl acetate (2×50 ml), then back into 1M hydrochloric acid (100 ml). The aqueous layer was washed with ethyl acetate (2×50 ml), then solid sodium hydrogen carbonate was added to pH 4. The product was extracted into dichloromethane (2×50 ml) and the combined organic layers were washed with brine (20 ml), dried over magnesium sulfate, filtered and evaporated to give the title compound (0.60 g, 24%).
Reaction SMILES: C(Cl)Cl.[CH3:4][C:5]1[N:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([NH2:13])[N:6]=1.Cl[S:15]([N:18]=[C:19]=[O:20])(=[O:17])=[O:16].[OH:21][CH:22]([C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26])[CH3:23]>C(OCC)C.C(N(CC)CC)C>[OH:21][CH:22]([C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH:26][S:15]([NH:18][C:19]([NH:13][C:7]1[N:6]=[C:5]([CH3:4])[N:10]=[C:9]([O:11][CH3:12])[N:8]=1)=[O:20])(=[O:17])=[O:16])[CH3:23]
Reactant: COc1nc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(O)c1ccccc1N
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)Nc2ccccc2C(C)O)n1

Procedure:
To 75 milliliters of methylene chloride maintained at 0°-5° C. via an ice bath were added 1.4 grams of 4-methyl-6-methoxy-2-amino-1,3,5-triazine and 1.55 grams of chlorosulfonyl isocyanate. After stirring for 3 hours at ice bath temperature a methylene chloride solution containing 1.0 gram of triethylamine and 1.37 grams of 2-(1-hydroxyethyl)aniline was added dropwise. The reaction mixture was removed from the ice bath, allowed to stir an additional one-half hour and then poured into 100 milliliters of 2 percent aqueous hydrochloric acid solution. After phase separation, the organic layer was washed in water and concentrated on a rotary evaporator affording a dark oil. Addition of diethyl ether to the dark oil resulted in the formation of a precipitate which was filtered-off. The filtrate was evaporated and the residue was taken-up in chloroform and again evaporated affording a powdery solid. Vacuum drying afforded 1.7 grams of light tan solid confirmed by NMR analysis as the desired product.