Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([CH:6]=O)=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[CH2:12]([O:15][C:16](=[O:28])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=1[N+:25]([O-])=O)[CH2:13][CH3:14].[BH3-]C#N.[Na+].CC(O)=O.O.[Cl-].[Na+].O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(#N)C.O>[CH2:12]([O:15][C:16](=[O:28])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH2:6][C:5]2[S:1][C:2]3[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=3[CH:4]=2)=[CH:20][C:19]=1[NH2:25])[CH2:13][CH3:14]
Reactant: O=Cc1cc2ccccc2s1
Reactant: CCCOC(=O)Nc1ccc(N)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: CCCOC(=O)Nc1ccc(NCc2cc3ccccc3s2)cc1N
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 10.1 %

Procedure:
Benzo[b]thiophene-2-carbaldehyde (1.36 g, 8.38 mmol) was added to a solution of (4-amino-2-nitro-phenyl)-carbamic acid propyl ester (2.00 g, 8.36 mmol) in acetonitrile (10 mL). The mixture was heated to 160° C. for 2 minutes in a 20 mL sealed microwave process vial. Upon cooling NaBH3CN (1.06 g, 16.7 mmol) and AcOH (48 μL, 0.84 mmol) were added and the mixture was stirred for 30 minutes at 25° C. Water/brine (1:1, 100 mL) was added and the mixture was extracted with ethyl acetate (3×100 mL). The organic phase was dried over magnesium sulphate, filtered and concentrated in vacuo. The crude intermediate was purified by flash chromatography on silica gel (eluent: ethyl acetate:heptane 1:9), and evaporated to dryness. The intermediate was then dissolved in tetrahydrofuran (20 mL) and Na2S2O4 (3.67 g, 21 mmol) dissolved in water (50 mL) was added. The resulting mixture was stirred at 40° C. for 5 hours under argon. The resulting mixture was extracted with ethyl acetate (3×100 mL), the combined organic phases dried over magnesium sulphate, filtered, and concentrated in vacuo. Purification by flash chromatography (eluent: ethyl acetate:heptane 1:1) furnished 0.3 g (10%) of the title compound as a solid. LC/MS (m/z) 356 ([M+H]+); RT=2.45 min. 1H NMR (CDCl3): 0.95 (t, 3H); 1.67 (m, 2H); 4.08 (t, 2H); 4.55 (s, 2H); 6.08 (d, 1H); 6.13 (dd, 1H); 6.93 (d, 1H); 7.20 (s, 1H); 7.27 (dt, 1H); 7.32 (dt, 1H); 7.68 (d, 1H); 7.77 (d, 1H).
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:45]1[C:46]([F:61])=[CH:47][CH:48]=[C:49]2[C:54]=1[N:53]=[C:52]([NH:55][C:56]1([CH3:59])[CH2:58][CH2:57]1)[C:51]([CH3:60])=[N:50]2.[CH3:62][C:63]1[NH:64][C:65](B2OC(C)(C)C(C)(C)O2)=[CH:66][C:67]=1[C:68]([O:70][CH2:71][CH3:72])=[O:69]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:61][C:46]1[C:45]([C:65]2[NH:64][C:63]([CH3:62])=[C:67]([C:68]([O:70][CH2:71][CH3:72])=[O:69])[CH:66]=2)=[C:54]2[C:49](=[CH:48][CH:47]=1)[N:50]=[C:51]([CH3:60])[C:52]([NH:55][C:56]1([CH3:59])[CH2:58][CH2:57]1)=[N:53]2
Reactant: CCOC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)[nH]c1C
Reactant: Cc1nc2ccc(F)c(Br)c2nc1NC1(C)CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cc(-c2c(F)ccc3nc(C)c(NC4(C)CC4)nc23)[nH]c1C
Yield: 51.1 %

Procedure:
A mixture of Xphos (Strem Chemicals, 0.169 g, 0.355 mmol), Pd2dba3 (Frontier Scientific, 0.162 g, 0.177 mmol), potassium phosphate tribasic monohydrate (Fluka, 2.450 g, 10.64 mmol), 8-bromo-7-fluoro-3-methyl-N-(1-methylcyclopropyl)quinoxalin-2-amine (610a) (0.880 g, 2.84 mmol), ethyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-carboxylate (417a) (0.99 g, 3.55 mmol) in dioxane (10.32 mL) and water (3.87 mL) was microwaved to 110° C. for 30 min. Reaction mixture was separated into two biphasic layers. The organic layer was loaded onto a silica gel samplet. Purification by biotage (0-100% EtOAc/hexanes) produced ethyl 5-(6-fluoro-2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-2-methyl-1H-pyrrole-3-carboxylate (417b) (0.555 g, 1.451 mmol, 41% yield). m/z (ESI, +ve) 383.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5](O)=[O:6].S(Cl)([Cl:16])=O>>[Br:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([Cl:16])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(F)c(F)c(Br)c1F
Product: O=C(Cl)c1cc(F)c(F)c(Br)c1F

Procedure:
A solution of the 3-bromo-2,4,5-trifluorobenzoic acid (2.5 g) in thionyl chloride (10 ml) was refluxed for 2.5 hours, and then concentrated. The resulting residue was purified by distillation through Widmer fractionating column to give the title compound (2.3 g), bp 98°-102° C./18 mmHg.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11]CC)=[O:10])=[C:5]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:4]=1.[C:22]1([CH2:28][C:29](Cl)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[C:5]([N:16]2[CH2:17][CH2:18][N:19]([C:29](=[O:30])[CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:20][CH2:21]2)[CH:4]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCOC(=O)COc1ccc(Cl)cc1N1CCNCC1
Agent: Cl
Product: O=C(O)COc1ccc(Cl)cc1N1CCN(C(=O)Cc2ccccc2)CC1

Procedure:
Prepared from the product from example 38 step c) and benzeneacetyl chloride by the method of Example 38 step d) to give the title compound as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18](=O)[N:19]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[CH2:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:14]=2)[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:35][O:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][N:19]([CH2:18][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][C@@H:8]([NH2:7])[CH2:17][CH2:16]3)[CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:33][CH:32]=1
Reactant: COc1ccc(CN(CC2CCOCC2)C(=O)c2ccc3c(c2)CC[C@H](NC(=O)OC(C)(C)C)C3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN(Cc2ccc3c(c2)CC[C@H](N)C3)CC2CCOCC2)cc1
Reaction time: 1 h

Procedure:
A mixture of {(S)-6-[(4-methoxybenzyl)(tetrahydropyran-4-ylmethyl)carbamoyl]-1,2,3,4-tetrahydronaphthalen-2-yl}carbamic acid tert-butyl ester (9.90 g) and dichloromethane (30 ml) was admixed cautiously with trifluoroacetic acid (2.2 g). After one hour, the reaction mixture was basified with saturated potassium carbonate solution. The organic phase was removed, dried over sodium sulfate and concentrated. The crude product was taken up in THF (300 ml) and treated according to method H with lithium aluminum hydride (reaction time 4 hours). The product was thus obtained with the molecular weight of 394.56 (C25H34N2O2); MS
Reaction SMILES: [N+:1]([C:4]1[C:9](Cl)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([O:14]CC)=[O:13])([O-:3])=[O:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>>[N+:1]([C:4]1[C:9]([O:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([OH:14])=[O:13])([O-:3])=[O:2]
Reactant: CCOC(=O)Cc1cccc(Cl)c1[N+](=O)[O-]
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(O)Cc1cccc(Oc2ccc(Cl)cc2)c1[N+](=O)[O-]
Yield: 54.6 %

Procedure:
A mixture of ethyl 2-(2-nitro-3-chlorophenyl)acetate (10 g.), 4-chlorophenol (7.8 g.), anhydrous potassium carbonate (8.5 g.) and cupric oxide (3 g.) was treated in a similar manner to the above Preparations to give 2-[2-nitro-3-(4-chlorophenoxy)phenyl]acetic acid (6.9 g.). mp 167° to 170° C.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.Cl.O>C1COCC1>[O:30]=[C:15]1[CH:16]=[C:17]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=2)[CH:18]=[CH:19][N:14]1[C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][CH:3]=[O:2])[N:6]=[CH:7]2
Reactant: COC(Cn1ncc2cc(-n3ccc(-c4ccc(C(F)(F)F)cc4)cc3=O)ccc21)OC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=CCn1ncc2cc(-n3ccc(-c4ccc(C(F)(F)F)cc4)cc3=O)ccc21
Yield: 233 %

Procedure:
A solution of 1-(1-(2,2-dimethoxyethyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)-phenyl)pyridin-2(1H)-one (480 mg, 1.08 mmol) in THF (10 mL) was treated with aqueous HCl (9 mL, 2.0 M). The solution was heated to reflux for 1 h, allowed to cool and then treated with H2O (100 mL). The resulting solids were isolated by filtration, washed with H2O and dried under high vacuum for 16 h to give the title compound (1.00 g, 64%) as a light brown solid: ESI MS m/z 398 [M+H]+.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:21])[C:4]([C:6]1[C:11]([NH2:12])=[N:10][CH:9]=[C:8](C2C=CC(Cl)=C(Cl)C=2)[N:7]=1)=[O:5].[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:25][C:24]=1B(O)O>>[CH3:1][O:2][N:3]([CH3:21])[C:4]([C:6]1[C:11]([NH2:12])=[N:10][CH:9]=[C:8]([C:24]2[CH:25]=[C:26]([S:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)(=[O:31])=[O:30])[CH:27]=[CH:28][C:23]=2[CH3:22])[N:7]=1)=[O:5]
Reactant: CON(C)C(=O)c1nc(-c2ccc(Cl)c(Cl)c2)cnc1N
Reactant: Cc1ccc(S(=O)(=O)N2CCOCC2)cc1B(O)O
Product: CON(C)C(=O)c1nc(-c2cc(S(=O)(=O)N3CCOCC3)ccc2C)cnc1N

Procedure:
This compound is prepared in an analogous manner to intermediate B substituting 3,4 dichlorophenyl boronic acid with 2-methyl-5-(N-morpholinylsulfonyl)phenyl boronic acid in step 2. The title compound is obtained as an off-white solid. [M+H]+ 422.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12](O)=[O:13])[N:9]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:6]2=[N:7][CH:8]=1.[CH:25]12[CH2:30][CH:29]1[CH2:28][N:27]([C:31]1[N:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1)[CH2:26]2>>[CH:29]12[CH2:30][CH:25]1[CH2:26][N:27]([C:31]1[N:36]=[CH:35][C:34]([NH:37][C:12]([C:10]3[N:9]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=4)[C:6]4=[N:7][CH:8]=[C:3]([C:2]([F:24])([F:1])[F:23])[CH:4]=[C:5]4[CH:11]=3)=[O:13])=[CH:33][CH:32]=1)[CH2:28]2
Reactant: O=C(O)c1cc2cc(C(F)(F)F)cnc2n1Cc1cccc(F)c1
Reactant: Nc1ccc(N2CC3CC3C2)nc1
Product: O=C(Nc1ccc(N2CC3CC3C2)nc1)c1cc2cc(C(F)(F)F)cnc2n1Cc1cccc(F)c1
Yield: 31.8 %

Procedure:
According to a method similar to that described in Stage 12.3, starting from 0.5 g (1.48 mmol) of 5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid, described in Stage 1.3, and 0.3 g (1.71 mmol) of 6-(3-azabicyclo[3.1.0]hex-3-yl)-3-aminopyridine, prepared in the preceding stage, we obtain 0.233 g of the expected product.
Reaction SMILES: ClCCl.B(Br)(Br)Br.[CH3:8][N:9]([CH:28]1[C:36]2[C:31](=[C:32]([OH:37])[CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1)[CH2:10][C:11]1[O:12][C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=1.Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].C([O-])([O-])=O.[K+].[K+]>ClCCl.CN(C=O)C>[CH3:8][N:9]([CH:28]1[C:36]2[C:31](=[C:32]([O:37][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1)[CH2:10][C:11]1[O:12][C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:15]=1
Reactant: CCOC(=O)CBr
Reactant: CN(Cc1nc(-c2ccccc2)c(-c2ccccc2)o1)C1CCc2c(O)cccc21
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)COc1cccc2c1CCC2N(C)Cc1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 0 °C
Reaction time: 4 h
Yield: 60.3 %

Procedure:
To a solution of 1-[N-methyl-N-[(4,5-diphenyloxazol-2.-yl)methyl]amino]-2,3-dihydro-4-methoxy-1H-indene (109 mg) in dichloromethane (2 ml) was added 1M boron tribromide dichloromethane solution (1 ml) at 0° C. After being stirred for 4 hours at 0° C., the solvent was evaporated in vacuo. The residue was extracted with ethyl acetate. The mixture was washed with brine, dried over MgSO4 and evaporated in vacuo to afford crude 1-[N-methyl-N-[(4,5-diphenyloxazol-2-yl)methyl]amino]-2,3-dihydro-4-hydroxy-1H-indene (109 mg). To a solution of crude 1-[N-methyl-N-[(4,5-diphenyloxazol-2-yl)methyl]amino]-2,3-dihydro-4-hydroxy-1H-indene (109 mg) and ethyl bromoacetate (80 mg) in DMF (3 ml) was added K2CO3 (80 mg). After being stirred for 24 hours, the solution was extracted with ethyl acetate. The mixture was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 1-[N-methyl-N-[(4,5-diphenyloxazol-2-yl)methyl]amino]-2,3-dihydro-4-ethoxycarbonylmethoxy-1H-indene (80 mg).
Reaction SMILES: CC1C=CC(C[S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=CC=1.Br[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC[O-].[Na+].SCC(OCC)=O>C(O)C>[CH2:17]([S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)CSCc1ccc(C)cc1
Reactant: BrCCc1ccccc1
Agent: CCOC(=O)CS
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSCCc1ccccc1

Procedure:
The procedure is as in Example 29 for the preparation of ethyl (4-methylbenzylthio)acetate, starting with (2-bromoethyl)benzene (20 g), a 2M ethanolic solution of sodium ethylate (25 cc) and ethyl 2-mercaptoacetate (13 g) in ethanol (150 cc). Ethyl (phenethylthio)acetate (21.7 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: C(B(CC)CC)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[N:24][CH:23]=[CH:22][N:21]=3)[N:18]=[C:17]([CH:26]([CH3:28])[CH3:27])[C:16]=2/[CH:29]=[CH:30]/[CH:31]([OH:41])[CH2:32][C:33](=[O:40])[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:11][CH:10]=1.C(O)(=O)C(C)(C)C.[BH4-].[Na+]>C1COCC1.CO>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[N:24][CH:23]=[CH:22][N:21]=3)[N:18]=[C:17]([CH:26]([CH3:27])[CH3:28])[C:16]=2[CH:29]=[CH:30][CH:31]([OH:41])[CH2:32][CH:33]([OH:40])[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:13][CH:14]=1
Reactant: CCOC(=O)CC(=O)CC(O)/C=C/c1c(C(C)C)nn(-c2cnccn2)c1-c1ccc(F)cc1
Agent: CC(C)(C)C(=O)O
Agent: CCB(CC)CC
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)CC(O)CC(O)C=Cc1c(C(C)C)nn(-c2cnccn2)c1-c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 5 h
Yield: 83.2 %

Procedure:
Triethyl borane (7.5 ml, 7.5 mmol) was added via syringe to a solution of the β-keto ester (3.17 g, 6.8 mmol, Step F) and pivalic acid (0.069 g, 0.68 mmol) in THF (50 ml) under a dry air atmosphere. The resulting orange solution was cooled to -78° C. and MeOH (10 ml) was added, followed by NaBH4 (0.28 g, 7.5 mmol). The resulting effervescent solution was stirred at -78° C. for five hours. The reaction was quenched by slowly pouring into ice cold H2O2 (5 ml, 30%) and allowing to stir overnight. The reaction was partitioned between H2O and CHCl3. The organics were washed extensively with H2O, dried (MgSO4) and evaporated to give 2.65 g (84%) of a yellow foam which was used in the next step without purification.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][C@@H:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[CH2:8]1.[NH3:27]>CO>[O:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][C@@H:9]2[CH2:10][CH2:11][N:7]([CH2:6][CH2:5][CH2:4][C:3]([NH2:27])=[O:2])[CH2:8]2)=[CH:14][CH:15]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N
Reactant: COC(=O)CCCN1CC[C@@H](Oc2ccc(Oc3ccccc3)cc2)C1
Solvent: CO
Product: NC(=O)CCCN1CC[C@@H](Oc2ccc(Oc3ccccc3)cc2)C1
Temperature: 100 °C
Yield: 74 %

Procedure:
4-[(R)-3-(4-Phenoxy-phenoxy)-pyrrolidin-1-yl]-butyric acid methyl ester (200 mg, 0.563 mmol) was taken into 7N Ammonia in methanol solution (5 mL) in a pressure tube. The tube was sealed and heated to 100° C. with stirring and left to react for 48 h. The reaction was concentrated to dryness, and purified by flash silica chromatography (20:1 silica ratio, eluted with a gradient of 10% methanol in dichloromethane to 15% methanol in dichloromethane) to provide the title product (141 mg, 74%); LCMS; m/z 341 (M+1); 1H NMR (400 MHz, DMSO) δ 1.62-1.68 (m, 2H), 1.75-1.78 (m, 1H), 2.06-2.10 (m, 2H), 2.22-2.25 (m, 1H), 2.35-2.43 (m, 3H), 2.59-2.68 (m, 2H), 2.80-2.84 (m, 1H), 4.80-4.83 (m, 1H), 6.69 (s, 1H), 6.89-6.93 (m, 4H), 6.94-6.98 (m, 2H), 7.05-7.09 (m, 1H), 7.24 (s, 1H), 7.32-7.36 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH:10]=[C:9]3[O:12][CH2:13][O:14][C:8]3=[CH:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].[N+:26](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O>CN(C)C=O>[NH2:26][N:5]1[C:6]2[CH:7]=[C:8]3[O:14][CH2:13][O:12][C:9]3=[CH:10][C:11]=2[C:2](=[O:1])[C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4]1
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CCOC(=O)c1cnc2cc3c(cc2c1O)OCO3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(N)c2cc3c(cc2c1=O)OCO3
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To a stirred mixture of 12.8 g (0.049 mole) of ethyl 8-hydroxy-1,3-dioxolo[4,5-g]quinoline-7-carboxylate and 13.5 g (0.098 mole) of potassium carbonate in 500 ml of dimethylformamide was added 11.7 g (0.059 mole) of O-(2,4-dinitrophenyl)hydroxylamine. The reaction mixture was stirred overnight at room temperature. An additional 5.0 g of O-(2,4-dinitrophenyl)hydroxylamine and 300 ml of dimethylformamide were then added and stirring was continued again overnight. The solvent was removed in vacuo, the residue stirred in 500 ml of water, and the product was collected by filtration and recrystallized from dimethylformamide to give 7.6 g of ethyl 5-amino-5,8-dihydro-8-oxo-1,3-dioxolo[4,5-g]quinoline-7-carboxylate, pale orange crystals, m.p. 251°-253° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:23])[CH2:3][N:4]([CH2:9][C@@H:10]1[NH:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1)[S:5]([CH3:8])(=[O:7])=[O:6].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([OH:40])([C:36]([F:39])([F:38])[F:37])[C:32]([F:35])([F:34])[F:33])=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:1][CH:2]([CH3:23])[CH2:3][N:4]([CH2:9][C@@H:10]1[N:15]([C:25]2[N:26]=[CH:27][C:28]([C:31]([OH:40])([C:32]([F:33])([F:34])[F:35])[C:36]([F:38])([F:39])[F:37])=[CH:29][N:30]=2)[CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:11]1)[S:5]([CH3:8])(=[O:6])=[O:7]
Reactant: CC(C)CN(C[C@H]1CN(C(=O)OC(C)(C)C)CCN1)S(C)(=O)=O
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)CN(C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1)S(C)(=O)=O
Temperature: 100 °C
Yield: 77.7 %

Procedure:
A 20-mL vial was charged with tert-butyl (3R)-3-(((2-methylpropyl)(methylsulfonyl)amino)methyl)-1-piperazinecarboxylate (0.498 g, 1.42 mmol, step 1), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.479 g, 1.71 mmol, Intermediate D), DIPEA (0.75 mL, 4.3 mmol) and 1,4-dioxane (5 mL). The mixture was heated at 100° C. for 12 h and then cooled to room temperature and partitioned between water (50 mL) and EtOAc (40 mL). The aqueous phase was extracted with EtOAc (40 mL) and the combined organic extracts were washed with saturated aqueous NaCl (60 mL) dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (50 g of silica gel, 0 to 50% EtOAc in hexanes) to afford tert-butyl (3R)-3-(((2-methylpropyl)(methylsulfonyl)amino)methyl)-4-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-1-piperazinecarboxylate (0.655 g) as a light-yellow foam.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([N:15]([CH2:22][CH3:23])[CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:14]>>[C:1]([N:19]1[CH2:20][CH2:21][CH:16]([N:15]([CH2:22][CH3:23])[CH2:13][CH3:14])[CH2:17][CH2:18]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCN(CC)C1CCNCC1
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N1CCC(N(CC)CC)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and 4-diethylaminopiperidine as starting raw materials, to produce an intended compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2].Br[CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17].C([O-])([O-])=O.[K+].[K+].C(OC1C=C(C=CC=1C)C=O)C>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[CH:7]=[O:8])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: CC(C)=CCBr
Agent: CCOc1cc(C=O)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)ccc1OCC=C(C)C

Procedure:
The title compound was prepared by reaction of 3-ethoxy-4-hydroxy-benzaldehyde with 1-bromo-3-methyl-2-butene in DMF using K2CO3 as base in analogy to the preparation of 3-ethoxy-4-methyl-benzaldehyde (intermediate D2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:20][C:21]([F:24])([F:23])[F:22])[S:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[C:4]([F:25])[CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.CC(C)([O-])C.[Na+].[N:65]1([C:71](=[O:73])[CH3:72])[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[C:71]([N:65]1[CH2:70][CH2:69][N:68]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:20][C:21]([F:24])([F:23])[F:22])[S:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:12])=[O:11])=[C:4]([F:25])[CH:3]=2)[CH2:67][CH2:66]1)(=[O:73])[CH3:72]
Reactant: O=S(=O)(Cc1ccccc1)N(Cc1ccc(Br)cc1F)CC(F)(F)F
Reactant: CC(=O)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2ccc(CN(CC(F)(F)F)S(=O)(=O)Cc3ccccc3)c(F)c2)CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 40.1 %

Procedure:
In a vial, N-[(4-bromo-2-fluoro-phenyl)methyl]-1-phenyl-N-(2,2,2-trifluoroethyl)methanesulfonamide (Example 2, step 2) (100 mg; 0.22 mmol), palladium(II) acetate (3 mg, 0.011 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (11 mg, 0.022 mmol) and sodium tert-butoxide (34 mg, 0.34 mmol) were weighed out and the vial was purged with nitrogen. 1,4-Dioxane (1 mL) and 1-piperazin-1-ylethanone (45 mg, 0.34 mmol) were then added and the reaction was stirred at 100° C. for 16 hours. The reaction was then filtered through diatomaceous earth, concentrated and purified by preparative reverse phase HPLC to yield 43 mg of N-(4-(4-acetylpiperazin-1-yl)-2-fluorobenzyl)-1-phenyl-N-(2,2,2-trifluoroethyl)methanesulfonamide. 1H NMR (400 MHz, DMSO) δ 7.44-7.34 (m, 5H), 7.27 (t, J=8.8 Hz, 1H), 6.83-6.71 (m, 2H), 4.53 (s, 2H), 4.34 (s, 2H), 3.86 (q, J=9.4 Hz, 2H), 3.63-3.52 (m, 4H), 3.24-3.20 (m, 2H), 3.18-3.11 (m, 2H), 2.03 (s, 3H); LCMS (m/z) ES+ 488.1 [M+1]+.