Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[CH:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@:9]1([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@:10](/[CH:24]=[CH:25]\[CH2:26]O)([OH:23])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>O>[CH2:1]([N:8]1[C@H:13]2[CH2:12][CH2:11][C@@:10]3([CH:24]=[CH:25][CH2:26][O:23]3)[C@:9]1([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:15][CH:14]2[C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C1C[C@]2(c3ccccc3)N(Cc3ccccc3)[C@H]1CC[C@]2(O)/C=C\CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C1C[C@]2(c3ccccc3)N(Cc3ccccc3)[C@H]1CC[C@@]21C=CCO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
The mixture of (1R*,2S*,5S*,6RS)-8-benzyl-6-(tert-butoxycarbonyl)-2-[(Z)-3-hydroxypropenyl]-1-phenyl-8-azabicylco[3.2.1]octan-2-ol (Description 26; a 3:1 mixture of C6 epimers, 4.0 g, 8.9 mmol), diethyl azodicarboxylate (1.8 ml, 11.4 mmol), triphenylphosphine (3.6 g, 13.7 mmol), tetrahydrofuran (30 ml) was stirred at room temperature for 15 minutes. The mixture was treated with water (0.1 ml) and concentrated in vacuo. The residue was treated with diethyl ether followed by iso-hexane. The solid was filtered off and the filtrate was concentrated and purified by chromatography on silica gel (iso-hexane:diethyl ether 0-20%) to give the title compound (3.1 g, 81%) as a 3:1 mixture of C6 epimers.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=O)[CH2:9][CH:8]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)[CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[C:18]([NH:21][NH2:22])([NH2:20])=[NH:19].[ClH:23].Cl.O>C(O)C>[ClH:23].[NH:21]([N:22]=[C:10]1[CH2:9][CH:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[CH2:7][C:6]2[N:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:11]1=2)[C:18]([NH2:20])=[NH:19]
Reactant: Cc1ccnc2c1C(=O)CC(c1nccs1)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1nccs1)C2
Yield: 96 %

Procedure:
A mixture of 4-methyl-7-(2-thiazolyl)-5,6,7,8-tetrahydroquinolin-5-one (0.68 g), aminoguanidine hydrochloride (0.37 g), concentrated hydrochloric acid (0.7 ml), water (0.7 ml) and ethanol (25 ml) was refluxed for 5 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added water. The mixture was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol-water to give 5-guanidinoimino-4-methyl-7-(2-thiazolyl)-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 118) (0.9 g) as colorless crystals.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([CH:9]1[CH:11]([C:12]([NH2:14])=O)[C:10]1([CH3:16])[CH3:15])(=[O:8])[CH3:7]>C1C=CC=CC=1>[C:6]([C@H:9]1[C@H:11]([C:12]#[N:14])[C:10]1([CH3:16])[CH3:15])(=[O:8])[CH3:7]
Reactant: CC(=O)C1C(C(N)=O)C1(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CC(=O)[C@H]1[C@H](C#N)C1(C)C

Procedure:
Phosphorus oxychloride (202.4 g, 1.32 m) was added dropwise to a solution of 3-acetyl-2,2-dimethyl-cyclopropane-1-carboxamide. (34.6 g, 0.22 m) in benzene (140 ml) and the resultant mixture refluxed for 3 hours. Excess reagents were removed in vacuo and the residue dissolved in ether (100 ml). The ether was washed with water (3×60 ml), dried over anhydrous magnesium sulphate and evaporated in vacuo to give a dark oil b.p. 72°-5° C./1.0 mm.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1.Cl[CH2:28][CH:29]([OH:31])[CH3:30]>>[CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:22][CH2:23][N:24]([CH2:28][CH:29]([OH:31])[CH3:30])[CH2:25][CH2:26]4)=[CH:19][CH:20]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: CC(O)CCl
Reactant: Cc1nc(C)c(-c2ccnc(Nc3ccc(N4CCNCC4)cc3)n2)s1
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(N4CCN(CC(C)O)CC4)cc3)n2)s1

Procedure:
By treatment of [4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl]-(4-piperazin-1-yl-phenyl)-amine with 1-chloro-2-propanol. 1H-NMR (CDCl3) δ: 1.10 (d, 3H, J=6.0 Hz, CH3), 2.26-2.33 (m, 2H, CH2), 2.49-2.53 (m, 2H, CH2), 2.61 (s, 3H, CH3), 2.63 (s, 3H, CH3), 2.76-2.80 (m, 2H, CH2), 3.07-3.13 (m, 4H, CH2), 3.83 (m, 1H, CH), 6.81 (d, 1H, J=4.4 Hz, pyrimidinyl-H), 6.88 (d, 2H, J=8.8 Hz, Ph-H), 7.02 (brs, 1H, OH), 7.44 (d, 2H, J=8.8 Hz, Ph-H), 8.30 (d, 1H, J=4.4 Hz, pyrimidinyl-H).
Reaction SMILES: Cl.C[O:3][C:4](=O)[CH:5]([CH2:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[NH2:6].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([CH2:7][CH:5]([CH2:4][OH:3])[NH2:6])(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: COC(=O)C(N)CS(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)CC(N)CO)cc1
Temperature: 0 °C
Yield: 55 %

Procedure:
Part C: To an ice cooled, stirred solution of (6.2 g, 20 mmol) of β-(4-methoxyphenylsulfonyl)-D,L-alanine methyl ester hydrochloride in tetrahydrofuran under nitrogen was added dropwise, (20 mL, 20 mmol) of lithium aluminum hydride in tetrahydrofuran. After 2 hours the ice cooled solution was carefully quenched by the addition of 5 mL of 10% sodium hydroxide and the resulting suspension was filtered through CELITE®. The filtrate was dried over magnesium sulfate filtered and concentrated to yield 2.7 grams of β-(4-methoxyphenyl-sulfonyl)-D,L-alaninol.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=3)[C@@H:13]([CH2:33][N:34]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[S:35]([CH3:38])(=[O:37])=[O:36])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH3:45]>CO>[NH2:45][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=3)[C@@H:13]([CH2:33][N:34]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[S:35]([CH3:38])(=[O:37])=[O:36])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: N
Reactant: CS(=O)(=O)N(C[C@H]1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1)c1ccccc1
Solvent: CO
Product: CS(=O)(=O)N(C[C@H]1CN(S(=O)(=O)c2ccc(N)nc2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1)c1ccccc1
Temperature: 140 °C

Procedure:
A 5-mL microwave vial was charged with N-(((2R)-4-((6-chloro-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-N-phenylmethanesulfonamide (0.134 g, 0.194 mmol, step 1) and 2M NH3 in MeOH (2 mL). The reaction mixture was heated in an Initiator microwave reactor (Biotage AB, Inc., Uppsala, Sweden) at 140° C. for 3 h. Then the mixture was then heated at 130° C. (thermal) for 12 h. The solvent was removed and the crude product was purified by column chromatography (25 g of silica gel, 10 to 90% EtOAc in hexanes) to afford N-(((2R)-4-((6-amino-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-N-phenylmethanesulfonamide (0.0385 g) as a white solid.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[SH:16].[OH:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([OH:26])[CH:25]=1)[CH:21]=O.C([O-])(=O)C.[Na+]>O.C(OCC)(=O)C>[F:15][C:12]([F:13])([F:14])[C:10]1[CH:9]=[CH:8][C:7]2[S:16][C:21]([C:20]3[CH:23]=[C:24]([OH:26])[CH:25]=[C:18]([OH:17])[CH:19]=3)=[N:5][C:6]=2[CH:11]=1
Reactant: Nc1cc(C(F)(F)F)ccc1S
Reactant: O=Cc1cc(O)cc(O)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Oc1cc(O)cc(-c2nc3cc(C(F)(F)F)ccc3s2)c1
Yield: 36.9 %

Procedure:
In an acetic acid (0.42 mL) solvent, a mixture including 2-amino-4-(trifluoromethyl)benzenethiol (100 mg, 0.44 mmol), 3,5-dihydroxybenzaldehyde (60 mg, 0.44 mmol), and sodium acetate (107 mg, 1.30 mmol) was refluxed for 6.5 hours. After cooling, the reaction mixture was distributed between ethyl acetate and water, and an organic layer was dried by using MgSO4, filtered, and evaporated under reduced pressure. The residual was purified by silica gel column chromatography using hexane and ethyl acetate (2:1) as a developer to obtain a solid Compound 36 (50.6 mg, 37%).
Reaction SMILES: [CH2:1]([N:6]1[CH2:11][CH2:10][CH2:9][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18]C)[CH:13]=2)[CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C(=O)=O.B(Br)(Br)Br.C([O-])([O-])=O.[Na+].[Na+].[ClH:33]>>[ClH:33].[CH2:1]([N:6]1[CH2:11][CH2:10][CH2:9][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN1CCCC(c2cccc(OC)c2)C1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])[O-]
Product: CCCCCN1CCCC(c2cccc(O)c2)C1
Reaction time: 1 h
Yield: 29 %

Procedure:
N-pentyl-3-(3-methoxyphenyl)piperidine (1.3 g, 0.005 mol) in CH2CL2 (20 ml) was cooled with dry ice and BBr3 (1.6 g, 0.006 mol) was added dropwise. The mixture was then held at -78° C. for 1 h and then allowed to reach r.t. overnight. The solution was made alkaline with aqueous Na2CO3, extracted with CH2Cl2 and the organic phase dried with Na2SO4. Evaporation of the solvent afforded an oily residue which was treated with HCl-saturated ethanol (5 ml). After evaporation of solvent, purification by extractions and recrystallization (ethanol/ether), the desired product (0.40 g, 29%) was obtained, mp. 70°-80° C.
Reaction SMILES: O[C:2]1[NH:3][C:4]2[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.P(Cl)(Cl)([Cl:14])=O.N>O>[Cl:14][C:2]1[NH:3][C:4]2[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1cccc2nc(O)[nH]c12
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Solvent: O
Product: Cc1cccc2nc(Cl)[nH]c12
Yield: 93 %

Procedure:
2-Hydroxy-4-methylbenzimidazole (5.92 g, 40 mmol) and 40 mL of phosphoryl chloride are introduced into a 250 mL two-necked flask under an argon atmosphere, with magnetic stirring. The mixture is refluxed for 20 hours and the phosphoryl chloride is evaporated off under vacuum. The solid obtained is taken up in water (250 mL), neutralized to pH=8 with 28% aqueous ammonia and the aqueous phase is extracted with ethyl acetate (3×250 mL). After the usual work-up, the title product is obtained in a yield of 93% (6.23 g). 1H NMR (300 MHz, δ ppm) DMSO D6: 2.47 (s, 3H), 7.01 (d, 1H), 7.11 (t, 1H), 7.32 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][O:9]/[N:10]=[C:11](/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)\[C:12]#[N:13])[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].C(=O)([O-])[O-].[K+].[K+]>CC(O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][N:10]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)/[C:12](=[N:21]/[OH:22])/[NH2:13])[CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#C/C(=N\OCc1cccc(N)n1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: N/C(=N\O)C(=NOCc1cccc(N)n1)c1ccccc1
Temperature: 80 °C
Yield: 110.6 %

Procedure:
To a suspension of (2Z)-{[(6-aminopyridin-2-yl)methoxy]imino}(phenyl)acetonitrile (4 g, 15.85 mmol, 1 eq.) in iPrOH/H2O (10/1, 110 ml) were added hydroxylamine hydrochloride (3.30 g, 47.56 mmol, 3 eq.) and potassium carbonate (6.57 g, 47.56 mmol, 3 eq.). The reaction was heated to 80° C. for 6 h and the solvent was evaporated to ¾th. The residue was extracted with EtOAc (3×50 ml) and washed with aq. sat. NaCl. The organics were combined, dried over MgSO4 and concentrated to give (Z)-2-{[(6-aminopyridin-2-yl)methoxy]imino}-N′-hydroxy-2-phenylethanimidamide (5 g, 99% yield) as a white solid.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[O:13][C:12]([CH2:19]I)([CH3:18])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CS(C)=O>[CH2:3]([N:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[O:13][C:12]([CH3:19])([CH3:18])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC1(C)CN(Cc2ccccc2)CC(C)(CI)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)CN(Cc2ccccc2)CC(C)(C)O1
Temperature: 100 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
Add solid NaBH4 (776 mg, 20.5 mmol) to a solution of 4-benzyl-2-iodomethyl-2,6,6-trimethyl-morpholine (6.22 g, 17.3 mmol) in DMSO (20 mL) and then heat the mixture at 100° C. After 2 h, add additional DMSO (10 mL). After an additional 1.25 h, add extra NaBH4 (120 mg, 3.17 mmol). Remove the heat after an additional 1.25 h (total reaction time=4.5 h). Quench the excess NaBH4 with 5 M HCl (20 ml). After 15 min, add 5 M NaOH (20 mL) and 1 M Na2S2O3 (20 mL) and then stir the mixture overnight. Dilute the mixture with tert-butyl methyl ether (250 mL) and water (100 mL). Separate the organic solution and wash with additional water (4×100 mL). Dry, filter and concentrate the organic solution. Purify the residue by flash chromatography, using a gradient from 50% to 100% CH2Cl2 in pentane as eluent. Dry the product so obtained briefly at 60° C. under vacuum to give the title compound (2.43 g, 60%) as a colorless liquid. 1H NMR (400 MHz, DMSO-d6): δ 7.2-7.4 (5H, m), 3.45 (2H, s), 2.12 (4H, s), 1.15 (12H, s).
Reaction SMILES: [OH-].[Na+].[C:3]([CH:7]([C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)[O:8][C:9]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:12]([CH2:18][N:19]2[C:27]3[CH:26]=[CH:25][N:24]=[C:23]([Cl:28])[C:22]=3[NH:21][CH2:20]2)=[CH:11][C:10]=1[CH2:29][CH2:30][CH3:31])([O:5]C)=[O:4]>CO.C(Cl)Cl>[C:3]([CH:7]([C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)[O:8][C:9]1[C:10]([CH2:29][CH2:30][CH3:31])=[CH:11][C:12]([CH2:18][N:19]2[C:27]3[CH:26]=[CH:25][N:24]=[C:23]([Cl:28])[C:22]=3[NH:21][CH2:20]2)=[CH:13][C:14]=1[CH2:15][CH2:16][CH3:17])([OH:5])=[O:4]
Reactant: CCCc1cc(CN2CNc3c2ccnc3Cl)cc(CCC)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCCc1cc(CN2CNc3c2ccnc3Cl)cc(CCC)c1OC(C(=O)O)c1ccc2c(c1)OCO2
Yield: 83.8 %

Procedure:
A 5N sodium hydroxide solution (0.1 mL) was added to a stirred mixture of the product of Step A (22 mg, 0.0410 mmol) in methanol (1mL). A few drops of methylene chloride were added to allow stirring then the mixture was stirred at room temperature for 2.5 h. The solvent was removed in vacuo then 5% citric acid solution added. The precipitate was filtered off, washed with water and dried in vacuo to give the titled carboxylic acid (18 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[NH3:38].CO>>[NH2:38][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F
Reactant: N
Solvent: CO
Product: Nc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Temperature: 80 °C
Yield: 27 %

Procedure:
A suspension of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (200 mg, 0.352 mmol) and ammonia in MeOH 7M (7 ml, 49.0 mmol) was heated in a sealed tube at 80° C. for 48 h. The reaction mixture was evaporated onto silica gel and chromatographed, 0-50% 1:9 acetone:CHCl3 in EtOAc. The resulting solid was triturated in MeOH to give the title compound (54 mg, 27% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.70 (br. s., 1H), 7.78 (d, J=5.3 Hz, 1H), 7.40-7.59 (m, 3H), 7.37 (td, J=7.4, 2.0 Hz, 1H), 7.14-7.31 (m, 2H), 6.52 (s, 2H), 5.58 (d, J=5.2 Hz, 1H), 3.66 (t, J=4.6 Hz, 4H), 3.40 (t, J=4.6 Hz, 4H). MS (ESI): 549.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=1[CH3:23])[O:9][CH2:8][CH2:7][CH:6]2[C:24]([O:26][CH3:27])=[O:25])#[N:2].C(Cl)(=O)C(Cl)=O.[F:34][C:35]([F:44])([F:43])[C:36]1[N:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C.O.CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](=[O:19])[NH:42][C:39]3[CH:40]=[N:41][C:36]([C:35]([F:44])([F:34])[F:43])=[CH:37][CH:38]=3)=[CH:16][C:15]=1[CH3:23])[O:9][CH2:8][CH2:7][CH:6]2[C:24]([O:26][CH3:27])=[O:25])#[N:2]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3C)c(C#N)cc21
Reactant: Nc1ccc(C(F)(F)F)nc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(C(F)(F)F)nc4)cc3C)c(C#N)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
4-(6-Cyano-4-(methoxycarbonyl)chroman-7-yloxy)-3-methylbenzoic acid (0.103 g, 0.280 mmol) was dissolved in 4 mL dry DCM at ambient temperature under nitrogen. Oxalyl chloride (0.0489 mL, 0.561 mmol) was added to the reaction followed by 10 μL DMF. The solution was stirred at ambient temperature for 1 hour. The solution was concentrated and the residue was taken up in 4 mL dry DCE. 6-(Trifluoromethyl)pyridin-3-amine (0.136 g, 0.841 mmol), pyridine (0.0567 mL, 0.701 mmol) and DMAP (0.0034 g, 0.0280 mmol) were added and the solution was stirred at ambient temperature overnight. The reaction was poured into water, extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel column chromatography, eluting with 30-50% ethyl acetate/hexanes, followed by a second silica gel chromatography eluting with 30% acetone/hexanes to provide the desired product (0.097 g, 68%).
Reaction SMILES: [C:1]([N:7]1[C@@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][O:9][C:8]1=[O:18])(=[O:6])/[CH:2]=[CH:3]/[CH2:4][CH3:5].[CH2:19]([N:26]([CH2:30][Si](C)(C)C)[CH2:27]OC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:19]([N:26]1[CH2:30][C@@H:3]([CH2:4][CH3:5])[C@H:2]([C:1]([N:7]2[C@@H:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:10][O:9][C:8]2=[O:18])=[O:6])[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CC/C=C/C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H]1CN(Cc2ccccc2)C[C@H]1C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
The compound from step 7b (490 mg, 2 mmol) was dissolved in methylene chloride (9 mL), and the solution was cooled to 0° C. and flushed with N2. N-benzyl-N-(methoxymethyl)trimethylsilylmethyl-amine (498 mg, 2.1 mmol) was added, the mixture was stirred for 20 minutes and trifluoroacetic acid (1M, 0.2 mL, 0.20 mmol) was added dropwise over 20 minutes with stirring at 0° C. The mixture was stirred at 0° C. for 1 hour and at room temperature for 24 hours, then diluted with 50 mL of methylene chloride, washed with 10% aqueous K2CO3 and dried over Na2SO4. The solvent was removed and the residue was dried under vacuum (767 mg). The isomers were separated by medium pressure liquid chromatography on silica gel, eluting with 0.5% methanol/methylene chloride. The major isomer (3R,4R) (290 mg) was taken to the next step. MS m/z 379 (M+H)+.
Reaction SMILES: C([O:3][C:4](OCC)([CH3:28])[C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[N:14]=2)[NH:9][CH:8]=1)=[O:6])C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:27][O:26][C:18]1[CH:17]=[C:16]([C:13]2[N:14]=[C:15]3[C:7]([C:5](=[O:6])[C:4](=[O:3])[CH3:28])=[CH:8][NH:9][C:10]3=[N:11][CH:12]=2)[CH:21]=[C:20]([O:22][CH3:23])[C:19]=1[O:24][CH3:25]
Reactant: CCOC(C)(OCC)C(=O)c1c[nH]c2ncc(-c3cc(OC)c(OC)c(OC)c3)nc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C(C)=O)c3n2)cc(OC)c1OC
Reaction time: 8 h

Procedure:
2,2-Diethoxy-1-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one (0.027 mg, 0.06 mM) was dissolved in 3 ml dichloromethane and 0.3 gm silica gel was added followed by 0.03 ml 10% aqueous citric acid solution. After stirring overnight 0.03 ml trifluoroacetic acid was added and stirred again overnight. To the orange mixture was added aqueous sodium bicarbonate, the mixture filtered and the silica gel rinsed with a methanol/dichloromethane mixture (20/80). The rinses were concentrate and the oil purified on a preparative thin layer chromatography plate eluting with methanol/dichloromethane (4/96). The product was dissolved in acetonitrile to induce crystallization, stripped and dried overnight at 2 torr in a vacuum oven at 60° C. to give 1-[2-(3,4,5-Trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propane-1,2-dione. (M+H)+=356.
Reaction SMILES: [OH-].[Na+].[C:3]12([C:13]3[CH:14]=[C:15]([NH:21][C:22](=[O:34])[NH:23][C:24]4[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=4)[CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2>CO>[C:3]12([C:13]3[CH:14]=[C:15]([NH:21][C:22](=[O:34])[NH:23][C:24]4[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=4)[CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[CH2:10][CH:9]3[CH2:11][CH:5]([CH2:6][CH:7]([CH2:8]3)[CH2:12]1)[CH2:4]2
Reactant: COC(=O)c1ccc(NC(=O)Nc2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(NC(=O)Nc2ccc(C(=O)O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.2 %

Procedure:
6 g (0.15 mol) of sodium hydroxide are added to a solution of 6.08 g (14 mmol) of methyl 4-[3-(1-adamantyl) -4-methoxyphenylureido]benzoate in 75 ml of methanol and the mixture is stirred at room temperature for 3 hours and then heated to reflux for 3.5 hours. The reaction mixture is evaporated, the residue is then taken up with 100 ml of water and the mixture is acidified to pH 1. The solid is filtered off, rinsed with water, dried and recrystallized in a tetrahydrofuran/hexane mixture to yield 2.78 g (87% ) of 4-[3-(1-adamantyl)-4-methoxyphenylureido]benzoic acid, melting point 279°-282° C.
Reaction SMILES: Br[CH2:2][CH:3](Br)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.CCCCCCCCCCCC>C(#N)C.CC(O)C.C(#N)C.C(SCCC)CC.C(#N)C.C(N(CC)CC)C>[CH2:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCC(Br)CBr
Agent: CCCSCCC
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: C=CCCCCCCCC

Procedure:
Solutions were prepared by dissolving all of the following in a total volume of 5 mL: (a) 32.7 mg of 1,2-dibromodecane, 18.3 mg of benzophenone and 10.0 mg of dodecane in acetonitrile(ACN)/methanol (15:85 v/v); (b) 24.2 mg 1,2-dibromodecane, 22.4 benzophenone and 10.0 mg dodecane in acetonitrile/2-propanol (15:85 v/v); (c) 22.7 mg 1,2-dibromodecane, 20.7 mg benzophenone and 10.0 mg dodecane in acetonitrile/propylsulfide (15:85 v/v); (d) 25.0 mg 1,2-dibromodecane, 21.5 mg benzophenone and 10.5 mg dodecane in acetonitrile/triethylamine (15:85 v/v). Two 2 mL aliquots of each solution were placed in quartz cells 7×7 mm2) and deaerated by bubbling oxygen-free nitrogen for 15 minutes. Samples were then irradiated at 350 nm using a photoreactor equipped with two RPR-350 lamps. Samples were rotated with a "merry-go-round" (to ensure that all samples received the same irradiation dose) and irradiated for 1.5 hours (methanol), 40 minutes (2-propanol), 30 minutes (propylsulfide) or 1 minute (triethylamine). A valerophenone solution (prepared as described above) was used as relative actinometer. Product (i.e. 1-decene) quantification and quantum yields were carried out as described above. Results are summarized in the table below. No 1-decene is formed (a) in the absence of benzophenone or (b) in the absence of the chain extender.