Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[C:35]5[NH:39][C:38](=[O:40])[O:37][N:36]=5)=[CH:25][CH:24]=4)=[C:18]([CH2:41][CH2:42][CH3:43])[N:17]=[C:16]3[CH3:44])=[CH:11][CH:10]=2)[CH2:4][CH:3]1[CH3:45].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[CH3:44][C:16]1[N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH:5]3[CH2:6][CH2:7][C:2](=[O:1])[CH:3]([CH3:45])[CH2:4]3)=[CH:10][CH:11]=2)[C:20](=[O:21])[C:19]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:39][C:38](=[O:40])[O:37][N:36]=3)=[CH:25][CH:24]=2)=[C:18]([CH2:41][CH2:42][CH3:43])[N:17]=1
Reactant: CCCc1nc(C)n(-c2ccc(OC3CCC(O)C(C)C3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC3CCC(=O)C(C)C3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 1 h
Yield: 76.3 %

Procedure:
To a solution of 3-{4-[(4-hydroxy-3-methylcyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (0.50 g) in methylene chloride (4 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.52 g), and the mixture was stirred for 1 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.38 g, 77%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]#[N:12])[CH:6]=[CH:7][C:8]=1[CH3:9].B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]#[N:12])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: COc1cc(CC#N)ccc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc(CC#N)cc1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a solution of 3-methoxy-4-methylphenylacetonitrile (2.0 g, 12.4 mmol) in dry CH2Cl2 (50 ml) cooled to −78° C., BBr3 1 M in CH2Cl2 (27 ml, 27 mmol) was added dropwise. The mixture was stirred overnight allowing the cooling bath to expire. The mixture was slowly poured in ice/water under stirring. When the ice melted, the aqueous phase was extracted with EtOAc and the organic phase was dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The crude title compound (1.7 g, 93% yield) was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.C(O[C:20](=[O:31])[NH:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]1)(C)(C)C.[Cl:32][C:33]1[C:43](C(O)=O)=[CH:42][C:36]2[NH:37][C:38](=[O:41])[CH2:39][S:40][C:35]=2[CH:34]=1>>[CH3:13][O:12][C:8]1[CH:9]=[C:10]2[C:5]([N:4]=[C:3]([CH3:14])[C:2]([O:30][CH2:29][CH2:28][N:25]3[CH2:24][CH2:23][CH:22]([NH:21][C:20]([C:43]4[C:33]([Cl:32])=[CH:34][C:35]5[S:40][CH2:39][C:38](=[O:41])[NH:37][C:36]=5[CH:42]=4)=[O:31])[CH2:27][CH2:26]3)=[N:11]2)=[CH:6][CH:7]=1
Reactant: O=C1CSc2cc(Cl)c(C(=O)O)cc2N1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Reactant: COc1ccc2nc(C)c(Cl)nc2c1
Product: COc1ccc2nc(C)c(OCCN3CCC(NC(=O)c4cc5c(cc4Cl)SCC(=O)N5)CC3)nc2c1

Procedure:
The title compound is prepared as a light yellow lyophilizated powder following Scheme 1 and in analogy to Example 1 using 3-chloro-6-methoxy-2-methyl-quinoxaline, [1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and 7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: [F:1][C:2]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6]C=1C#N.S(=O)(=O)(O)[OH:12].[O:16]1[CH2:21][CH2:20]OCC1>>[F:1][C:2]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:20]=1[C:21]([OH:16])=[O:12]
Reactant: C1COCCO1
Reactant: N#Cc1cccc(I)c1F
Reactant: O=S(=O)(O)O
Product: O=C(O)c1cccc(I)c1F
Temperature: 115 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
A mixture of 2-fluoro-3-iodobenzonitrile (preparation 22a, 5.00 g, 20.2 mmol), dioxane (16 mL) and sulphuric acid (25 mL) was heated to 115° C. After 4 hours, the mixture was cooled and filtered. Water was added to the filtrate and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSO4) and evaporated to give the title compound (4.42 g, 82%) as a solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[NH:14][CH2:13][CH2:12][CH2:11][N:10]3[C:15](=[O:17])[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Cl[C:71]1[CH:76]=[CH:75][N:74]=[C:73]([S:77][CH3:78])[N:72]=1>C1(C)C=CC=CC=1>[CH3:78][S:77][C:73]1[N:74]=[C:75]([N:14]2[CH2:13][CH2:12][CH2:11][N:10]3[C:15](=[O:17])[CH:16]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:8]=[C:9]23)[CH:76]=[CH:71][N:72]=1
Reactant: CSc1nccc(Cl)n1
Reactant: O=c1cc(-c2ccccc2)cc2n1CCCN2
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CSc1nccc(N2CCCn3c2cc(-c2ccccc2)cc3=O)n1
Temperature: 70 °C

Procedure:
To a mixture of 8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one (1.86 g, 8.23 mmol), sodium tert-butoxide (1.6 g, 16 mmol), BINAP (0.15 g, 0.207 mmol), and Pd (OAc)2 (55 mg, 0.2 mmol) was added toluene (20 mL) and 4-chloro -2-methylthiopyrimidine (1.5 mL, 12 mmol). After purged with N2 for 10 min, the overall mixture was heated at 70° C. for 3 h prior to being cooled to room temperature. The resulting material was diluted with saturated NHCl(aq), water, and DCM. The organic layer was taken and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4, filtrated, and concentrated. Column chromatographic purification (3% MeOH in DCM) of the crude residue afforded the title compound as a yellow solid. MS m/e 351 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:8])([CH3:7])[CH2:5][OH:6].Br[CH2:10][C:11]([OH:13])=[O:12]>C1COCC1>[CH3:3][C:4]([CH3:8])([CH3:7])[CH2:5][O:6][CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C(O)CBr
Reactant: CC(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)COCC(=O)O
Reaction time: 0.08 h

Procedure:
NaH (40% oil dispersion, 432 mg) was added to a solution of 2,2-dimethylpropan-1-ol (0.319 ml) in THF (15 ml) at 0° C. After stirring for 5 min, 2-bromoacetic acid (500 mg) was added. The mixture was refluxed under Ar atmosphere for 2 h. The mixture was quenched with water, washed with EtOAc, acidified with 1 M HCl (11 ml) and extracted with EtOAc. The organic layer was separated, dried over MgSO4 and concentrated in vacuo to give the title compound (490 mg) as a pale pink oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:5][C:6](C)=[CH:7][C:8](=[O:18])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O[CH:21](C1OC=CC(=O)C=1OCC1C=CC=CC=1)C>>[CH3:1][O:2][CH:3]([C:4]1[O:5][CH:6]=[CH:7][C:8](=[O:18])[C:9]=1[O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:21]
Reactant: CC(O)c1occc(=O)c1OCc1ccccc1
Reactant: COCc1oc(C)cc(=O)c1OCc1ccccc1
Product: COC(C)c1occc(=O)c1OCc1ccccc1
Yield: 92.3 %

Procedure:
In an analogous procedure in the preparation of 2-methoxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one using 2-(1-hydroxyethyl)-3-benzyloxy-pyran-4(1H)-one (2.46 g, 10 mmol, 1 eq.) yielded the title compound as a yellow oil (2.4 g, 92.3%). Further purification by column chromatography on silica gel (eluant: EtOAc) furnished the pure product (2.1 g, 80.8%) as a bright yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:8]2[NH:9][C:10]3[CH:11]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:14][C:15]=3[C:7]=2[C:6](=O)[NH:5][CH:4]=1)#[N:2].P(Cl)(Cl)([Cl:23])=O>O1CCOCC1>[CH3:19][O:18][C:16]([C:12]1[CH:13]=[CH:14][C:15]2[C:7]3[C:6]([Cl:23])=[N:5][CH:4]=[C:3]([C:1]#[N:2])[C:8]=3[NH:9][C:10]=2[CH:11]=1)=[O:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc2c(c1)[nH]c1c(C#N)c[nH]c(=O)c12
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(c1)[nH]c1c(C#N)cnc(Cl)c12
Temperature: 93 °C
Reaction time: 5 h

Procedure:
A stirred slurry of methyl 4-cyano-1-oxo-2,5-dihydro-1H-pyrido[4,3-b]indole-7-carboxylate (1.000 g, 3.74 mmol) in Dioxane (Volume: 25 mL) was heated to 93° C. Phosphorus oxychloride (1.713 mL, 18.71 mmol) was added slowly dropwise over 30 minutes. After complete addition the reaction mixture was stirred at 93° C. for 5 hours then at room temperature overnight. LC-MS showed complete conversion to the desired product mass with minor by-products. The reaction mixture was diluted with 25 ml ethyl acetate and filtered. The filtrate was concentrated under vacuum to give 1.311 g crude solid tan product. The crude product was washed with diethyl ether, then triturated with acetonitrile and filtered to give Methyl-1-chloro-4-cyano-5H-pyrido[4,3-b]indole-7-carboxylate as a tan solid [0.855 g, 2.99 mmol, 80% yield]. The product had an HPLC Retention Time=3.658 min [4 min grad, 10% MeOH/water to 90% MeOH/water, 0.1% TFA, YMC COMBISCREEN® ODS-A, 4.6×50 mm, 220 nM]; LC/MS+1 286.1
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[C:5](=O)[C:6](=O)[CH3:7])[CH3:2].[NH2:11][CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.C(#[N:21])C>>[CH3:7][C:6]1[NH:21][C:12]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:11][C:5]=1[C:4]([O:3][CH2:1][CH3:2])=[O:10]
Reactant: CC#N
Reactant: CCOC(=O)C(=O)C(C)=O
Reactant: NCc1cccnc1
Product: CCOC(=O)c1nc(-c2cccnc2)[nH]c1C
Temperature: -10 °C

Procedure:
A solution of 16 g of 2,3-dioxobutyric acid ethyl ester, (Z)-2-oxime, 12 g of 3-aminomethylpyridine and 100 ml of acetonitrile was stirred at reflux for 4 hours, then clarified while hot and the filtrate cooled at -10° C. The resulting precipitate was collected, washed with acetonitrile, air dried and recrystallized from acetonitrile at -10° C., giving 4.8 g of 5-methyl-2-(3-pyridinyl)-1H-imidazole-4-carboxylic acid, ethyl ester.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[SH2:11].[K].Cl>>[SH:11][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: S
Reactant: Clc1cccc2nccn12
Agent: Cl
Agent: [K]
Product: Sc1cccc2nccn12
Temperature: 25 °C
Reaction time: 6 h
Yield: 33 %

Procedure:
A mixture of 2.5 g of 5-chloroimidazo[1,2-a]pyridine and 30 ml of 2N-potassium hydrogen sulfide solution is stirred at room temperature for 6 hours and then at 80° C. for 3 days. The pH of the reaction mixture is adjusted to 2 with concentrated hydrochloric acid. The reaction mixture is extracted twice with 200 ml of ethyl acetate, and dried over magnesium sulfate, followed by evaporation of the solvent under reduced pressure, and the resulting powder is collected by filtration. Yield:33%.
Reaction SMILES: [OH:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:19]=3[C:29]([F:32])([F:31])[F:30])[O:15][N:14]=2)=[CH:9][CH:8]=1)([CH3:6])[C:3](O)=[O:4].CN1CCOCC1.CN(C(O[N:48]1N=[N:55][C:50]2C=CC=N[C:49]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:49]([CH2:50][NH:55][C:3](=[O:4])[C:2]([OH:1])([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:19]=3[C:29]([F:32])([F:31])[F:30])[O:15][N:14]=2)=[CH:9][CH:8]=1)[CH3:6])#[N:48]
Reactant: CC(O)(C(=O)O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(O)(C(=O)NCC#N)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 20.16 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid (Int-XV, (30 mg, 0.067 mmol), 4-methylmorpholine (27.3 mg, 0.269 mmol), and HATU (33.3 mg, 0.088 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 25 mL/min, 220 nM, product retention=30.21 min) to provide (R/S)-N-(cyanomethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanamide (7 mg, 0.014 mmol, 20.16% yield): LCMS=484.0 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.81 (1 H, t, J=5.83 Hz), 8.11-8.23 (2 H, m), 7.51-7.92 (7 H, m), 4.04-4.23 (2 H, m), 1.81 (3 H, s); HPLC peak RT=10.0 min (Method A).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:29]2[S:30][C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[N:33]=2)=[C:5]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]=1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[Na].[OH-:39].[K+]>O1CCOCC1>[CH2:8]([O:7][C:6]1[C:5]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:4]([C:29]2[S:30][C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[N:33]=2)[S:3][C:2]=1[C:2]1[S:3][C:4]([C:29]2[S:30][C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[N:33]=2)=[C:5]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]=1[O:39][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: [OH-]
Reactant: CCCCCCCCCCOc1c(Br)sc(-c2nc3ccccc3s2)c1OCCCCCCCCCC
Agent: [K+]
Agent: [Na]
Solvent: C1COCCO1
Product: CCCCCCCCCCOc1c(-c2nc3ccccc3s2)sc(-c2sc(-c3nc4ccccc4s3)c(OCCCCCCCCCC)c2OCCCCCCCCCC)c1OCCCCCCCCCC
Temperature: 100 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
A solution of 2-bromo-3,4-bis(decyloxy)-5-(benzothiazol-2-yl)-thiophene (12.2 g 20 mmol), and hexabutyl ditin (5.8 g, 10 mmol) in dioxane (100 ml), (freshly distilled from sodium after treatment with potassium hydroxide), was degassed by bubbling nitrogen through the solution for 20 min. Under nitrogen, tetrakistriphenylphosphinopalladium (0.468 g) was added and the mixture was heated at 100° C. for 20 hr. After cooling, pyridine (5 ml) was added and the resulting mixture allowed to stand for 1 hr. The separated solids were filtered and the filtrate diluted with an equal volume of water. The mixture was extracted with an equal volume of toluene, dried over magnesium sulfate and concentrated. The residue was combined with the initial solids and chromatographed over 250 g of silica gel. Elution with 3:1 and 2:1 heptane:toluene gave the desired product which was recrystallized from heptane to give 7.02 g (66.5% yield) mp 93.9°-95° C. Mass Spec. m/z 916 (M+ --C10H20). Elemental Analysis: Calculated for C62H92N2O4S4 : C, 70.36, H, 8.77, N, 2.65, and S, 12.10%. Found: C, 69.98, H, 8.90, N, 2.59, and S, 11.98 %.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[NH2:20][CH2:21][CH:22]1[CH:26]([CH3:27])[CH2:25][NH:24][CH2:23]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:20][CH2:21][CH:22]1[CH:26]([CH3:27])[CH2:25][N:24]([C:10]2[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=2[F:15])[CH2:23]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: CC1CNCC1CN
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC(C)C(CN)C3)c(F)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.9 %

Procedure:
A mixture of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.5 g), anhydrous acetonitrile (5 ml), 3-aminomethyl-4-methylpyrrolidine (0.22 g) and DBU (0.28 g) was refluxed for an hour and then stirred at room temperature for 3 hours. The resulting precipitate was collected by filtration and washed with ether to give the title compound (0.39 g) as pale yellow powder, mp 222°-224° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11])=[CH2:3].C(Cl)Cl.[NH2:19][C:20]1[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=1.C1N2CCN(CC2)C1>>[CH3:27][C:22]1[CH:23]=[C:24]([CH3:26])[N:25]=[C:20]([NH:19][C:14]([NH:13][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:2]([CH3:1])=[CH2:3])(=[O:12])=[O:11])=[O:15])[N:21]=1
Reactant: Cc1cc(C)nc(N)n1
Reactant: C=C(C)c1ccccc1S(=O)(=O)N=C=O
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: C=C(C)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(1-methylethenyl)benzenesulfonyl isocyanate in methylene chloride (0.9 g, 4 mmol active ingredient) was added via syringe to a nitrogen purged flask containing a 2-amino-4,6-dimethylpyrimidine and a trace (ca. 10 mg) of DABCO. The mixture was heated to reflux for 3 hours then stirred at room temperature overnight. Evaporation of the mixture left a semi-solid residue that was triturated with ether and filtered. In this manner 0.95 g of the title compound was obtained, m.p. 177°-183°.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[N:16]=[CH:15][C:14](I)=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[F:20][C:21]([F:26])([F:25])C([O-])=O.[Na+].O.ClCCl>CN1CCCC1.[Cu]I>[F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[N:16]=[CH:15][C:14]([C:21]([F:26])([F:25])[F:20])=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(I)cnc1Oc1ccc(F)cc1
Reactant: O=C([O-])C(F)(F)F
Agent: [Cu]I
Agent: CN1CCCC1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(C(F)(F)F)cnc1Oc1ccc(F)cc1
Temperature: 160 °C
Reaction time: 16 h
Yield: 10.2 %

Procedure:
A mixture of methyl 2-(4-fluorophenoxy)-5-iodonicotinate (step 1, 373 mg, 1.0 mmol), sodium trifluoroacetate (1.36 g, 10 mmol), and copper(I) iodide (960 mg, 5.0 mmol) in 1-methyl-pyrolidine (8.0 mL) was stirred at 160° C. for 16 h under nitrogen atmosphere. The reaction mixture was poured into water (20 mL) and extacted with dichloromethane (50 mL×3). The combined organic extracts were washed with brine (50 mL) and dried (sodium sulfate). After removal of the solvent, the residue was purified by TLC plate developing with hexane/ethyl acetate (1/1) to afford 32 mg (10%) of the title compound: 1H-NMR (CDCl3) δ 8.5 (2H, s), 7.13 (1H, d, J=6.3 Hz), 3.99 (3H, s); MS (ESI) m/z 316 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([CH3:11])[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[CH:4][CH:3]=1.O=S(Cl)Cl.[NH2:23][C:24]1[C:25]([F:32])=[C:26]([OH:31])[CH:27]=[CH:28][C:29]=1[F:30].C([O-])(O)=O.[Na+]>C1COCC1.O>[F:32][C:25]1[C:26]([OH:31])=[CH:27][CH:28]=[C:29]([F:30])[C:24]=1[NH:23][C:8](=[O:10])[C:7]1[C:2]([F:1])=[CH:3][CH:4]=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:6]=1[CH3:11]
Reactant: Cc1c(-c2cccc(F)c2)ccc(F)c1C(=O)O
Reactant: Nc1c(F)ccc(O)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1c(-c2cccc(F)c2)ccc(F)c1C(=O)Nc1c(F)ccc(O)c1F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 11.1 %

Procedure:
To 6-fluoro-3-(3-fluorophenyl)-2-methyl-benzoic acid (3 g, 12.0 mmol, 1 eq) was added SOCl2 (60 mL) and the reaction heated at 80° C. overnight. The resulting mixture was concentrated in vacuo and the residue that remained dissolved in THF (20 mL) and added dropwise to a mixture of 3-amino-2,4-difluoro-phenol (1.93 g, 13.2 mmol, 1.1 eq) and NaHCO3 (2.32 g, 36.2 mmol, 3 eq) in THF (5 mL). After the addition, the reaction mixture was stirred at room temperature for 30 min. Water was added and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo to give the title compound (500 mg, 11%) which was used without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][N:16]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[Cl:37])[C:17]([CH:19]1[C:24](=O)[C@:23]2([CH3:29])[C:26]([CH3:28])([CH3:27])[C@H:20]1[CH2:21][CH2:22]2)=[O:18])=O)(C)(C)C>ClCCl>[Cl:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[N:16]1[C:17](=[O:18])[C:19]2[C@H:20]3[C:26]([CH3:27])([CH3:28])[C@:23]([CH3:29])([CH2:22][CH2:21]3)[C:24]=2[NH:15]1
Reactant: CC(C)(C)OC(=O)NN(C(=O)C1C(=O)[C@@]2(C)CC[C@@H]1C2(C)C)c1ccc(F)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3Cl)c(=O)c12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Trifluoroacetic acid (15 mL) was added in two portions to a cooled (0° C.) solution of N′-(2-chloro-4-fluoro-phenyl)-N′-((1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (˜7.2 mmol) in dichloromethane (15 mL). The reaction mixture was stirred at 0° C. for 5 min and then at room temperature for 2 h. The reaction mixture was evaporated (using high vacuum in the end). Dichloromethane (100 mL) was added to the residue and the solution was washed with water (4×50 mL), and brine (50 mL), dried (magnesium sulfate), filtered, and evaporated to give (4R,7S)-2-(2-chloro-4-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (2.6 g, 113% of the expected amount) as a tan solid. This was used directly in subsequent steps without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[C:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([I:23])[CH:21]=2)[NH:16][CH:15]=1)=[O:13].C(OCC)(=O)C.O1CCCC1.C(=O)(O)[O-].[Na+]>O>[NH2:8][C:7]1[C:2]([F:1])=[C:3]([C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([I:23])[CH:21]=3)[NH:16][CH:15]=2)=[O:13])[C:4]([F:11])=[CH:5][CH:6]=1
Reactant: O=C(c1c(F)ccc([N+](=O)[O-])c1F)c1c[nH]c2ncc(I)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(I)cc23)c1F
Temperature: 60 °C
Yield: 87.3 %

Procedure:
In a reaction vial, (2,6-difluoro-3-nitro-phenyl)-(5-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (45, 0.123 g, 0.287 mmol) is mixed with 5.0 mL of ethyl acetate and 5.0 mL of tetrahydrofuran. Stannous chloride, dehydrate (0.223 g, 0.989 mmol) is added and the reaction is heated at 60° C. for 24 hours. The reaction is poured into a mixture of 25 mL of water and 25 mL of saturated aqueous sodium bicarbonate and treated with celite, then filtered through a bed of celite. The celite is washed with ethyl acetate. The organic layer is separated and washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with ethyl acetate and dichloromethane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (46, 0.100 g). MS (ESI) [M+H+]+=399.9.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1.[CH3:15][Si:16]([CH3:23])([CH3:22])[CH2:17][CH2:18][O:19][CH2:20]Cl.P([O-])([O-])([O-])=O>CN(C=O)C.C(OCC)(=O)C>[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([S:11]([N:14]([CH2:20][O:19][CH2:18][CH2:17][Si:16]([CH3:23])([CH3:22])[CH3:15])[CH2:20][O:19][CH2:18][CH2:17][Si:16]([CH3:23])([CH3:22])[CH3:15])(=[O:12])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: NS(=O)(=O)c1cccc(CO)c1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(CO)c1
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% oil dispersion, 0.315 g) was added to 3-hydroxymethylbenzenesulfonamide (0.67 g) with stirring in DMF (20 ml) under nitrogen at 20°. After 15 min, 2-(trimethylsilyl)ethoxymethyl chloride (1.27 ml) was added and stirring was continued for 1.5 h. pH 6.4 Phosphate buffer and ethyl acetate were added. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were washed twice with brine, dried (MgSO4) and evaporated to an oil. This oil in dichloromethane was loaded onto a column of silica gel (75 g) set up in 10% ethyl acetate in 40-60 petroleum ether. The column was run with this, then 20%, 30% and 50% ethyl acetate in 40-60 petroleum ether to give the title compound (0.74 g) LCMS RT=4.00 min.